Survivors of childhood acute lymphoblastic leukemia (ALL) and malignant brain tumors (BTs) are at significant risk for cognitive impairments secondary to disease and treatment-related factors (e.g., Moleski, 2000; Mulhern & Bulter, 2004; Ris & Noll, 1994). Global cognitive declines, including declines on measures of intellectual functioning and academic achievement, are well established (e.g., Moore, 2005; Mulhern & Butler, 2004). Recent empirical findings suggest attention and/or working memory impairments are proximal contributors to these global declines (Reddick et al., 2003; Rogers, Horrocks, Gritton, & Kernahan, 1999; Schatz, Kramer, Ablin, & Matthay, 2000). Attention problems occur frequently among childhood cancer survivors, with estimates of approximately one-quarter of ALL survivors demonstrating significant dysfunction (Krull et al., 2008). Impairment in attentional processes has been shown to explain a significant proportion of the relationship between treatment-related neurological changes and subsequent declines in the intellectual and academic functioning of cancer survivors (Reddick et al., 2003). Cognitive impairments in childhood cancer survivors are of significant concern as they are associated with academic difficulties, high unemployment rates and a reduced quality of life (e.g., Haupt et al., 1994; Mostow, Byrne, Connelly, & Mulivhill, 1991). Despite these well-established findings, there have been few empirically validated interventions to remediate cognitive impairments emerging secondary to treatment for childhood cancer (for a review, see Butler & Mulhern, 2005). Stimulant medications have been used for decades to successfully treat otherwise healthy children diagnosed with attention deficit hyperactivity disorder (ADHD; American Psychiatric Association, 1994; Brown & Daly, in press; Gadow, 1992). The most commonly prescribed medication for ADHD is methylphenidate (MPH), a piperidine derivative that acts by releasing dopamine from presynaptic vesicles, reducing dopamine reuptake and inhibiting monoamine oxidase (Guevara, Lozano, Wickizer, Mell, & Gephart, 2002; Robison, Sclar, Skaer, & Balin, 1999; Safer, Zito, & Fine, 1996). The most consistent benefits of MPH have been demonstrated on measures of attention and concentration, as well as observable classroom and social behavior (Brown et al., 2005). The majority of children treated with stimulant medications experience some adverse side effects; these are usually mild to moderate, and dose dependent (Brown & Daly, in press). Controlled clinical trials directly comparing MPH, amphetamines, and dextroamphetamine have not revealed group differences in efficacy or safety (Arnold, 2000; Brown et al., 2005; Grcevich, Rowane, & Marcellino, 2001; Wolraich, et al., 2001). Children who are neurologically compromised may evidence less response to MPH and a higher frequency of adverse effects in relation to healthy peers (Weber & Lutschg, 2002) such that the ADHD literature may not be generalizable to childhood cancer survivors. The first randomized, double-blind, placebo-controlled between-groups trial of MPH in childhood cancer survivors was conducted by Thompson and colleagues (2001). Significant improvement was demonstrated on a continuous performance measure of sustained attention but not on measures of verbal memory or visual–auditory association. The same group of investigators later reported on 83 childhood cancer survivors who participated in a 3-week, placebo-controlled, double-blind, crossover study comparing low (0.3 mg/kg) and moderate (0.6 mg/kg) dose MPH to placebo (Mulhern et al., 2004). Significant improvement on MPH relative to placebo was noted on parent and teacher ratings of attention and teacher ratings of social skills. In this study, medication response was defined at the group rather than at the individual level, and factors predictive of a positive medication response were not evaluated. We are not aware of any studies that have investigated predictors of stimulant medication response in childhood cancer survivors. A seminal paper by Barkley that includes a comprehensive review of medication response in children diagnosed with ADHD indicates that approximately 75% of “hyperkinetic” children receiving stimulant medications respond favorably while the remaining 25% are unchanged or made worse (Barkley, 1977). This rate is consistent with more recent controlled clinical trials in children with ADHD; for example, Efron, Jarman, and Barker (1998) found an MPH response rate of 72% and Greenhill et al. (2001) found an MPH response rate of 77%. However, studies indicate that response rate can vary from approximately 50–80% depending on how rigorously medication response is defined (e.g., clinical judgment, arbitrary percent change in symptoms, or statistically derived threshold; Buitelaar, Van der Gaag, Swaab-Barneveld & Kuiper, 1995; Chabot, Orgill, Crawford, Harris, & Serfontein, 1999; Zeiner, Bryhn, Bjercke, Truyen, & Strand, 1999) and whether children diagnosed with ADHD are demonstrating significant overactivity (Chabot et al., 1999). The ADHD literature has revealed that the most consistent predictors of a positive medication response include higher levels of attention impairment on performance measures or behavioral ratings (Buitelaar et al., 1995; Chabot et al., 1999; Hermens, Cooper, Kohn, Clarke, & Gordon, 2005; Thomson & Varley, 1998); higher levels of hyperactivity based on parent or teacher ratings, clinical interviews, or direct observation (Denney & Rapport, 1999; Hermens et al., 2005; Zeiner et al., 1999); younger age (Buitelaar et al., 1995; Thomson & Varley, 1998; Zeiner et al., 1999); and higher intellectual functioning (Aman, 1996; Aman, Buican & Arnold, 2003; Buitelaar et al., 1995; Thomson & Varley, 1998). The most consistent predictor of a negative stimulant medication response is comorbidity of internalizing psychopathology (Buitelaar et al., 1995; DuPaul, Barkley, & McMurray, 1994; Pliszka, 1998; Zeiner et al., 1999). The literature is inconsistent with respect to the predictive value of comorbid externalizing psychopathology (Hechtman, 1999; Pliszka, 1998; Thomson & Varley, 1998). Demographic factors including gender, years of education, and socioeconomic status have generally not been predictive of medication response (Hermens et al., 2005; Spencer et al., 2005). In the current study, we expand upon the existing literature by reporting on the results of a randomized, double-blind, placebo-controlled, crossover study assessing the benefits of MPH for learning-impaired cancer survivors based on parent and teacher ratings of attention. Given not all cancer survivors are likely to respond to MPH, and the need to balance response with adverse side effects in a vulnerable population, it is of significant clinical advantage to identify prior to treatment those patients most likely to benefit from MPH. Accordingly, the primary goals of this investigation were to evaluate the rate of MPH response in cancer survivors and to identify specific factors predictive of a positive medication response. Based on a demonstrated lower MPH response rate in children with comorbid ADHD and learning disabilities (Grizenko, Bhat, Schwartz, Ter-Stepanian, & Jooper, 2006), we hypothesized that the response rate in this study would be lower than the 75% reported in the ADHD literature. Using the ADHD literature as a guide, we also hypothesized that higher levels of inattention and hyperactivity, younger age, and higher intellectual functioning would be predictive of a positive medication response. We further predicted that those children most likely to have had significant neurological impairment secondary to disease and treatment (i.e., BT diagnosis, younger age at treatment, and increased intensity of CNS-directed therapy, i.e., radiation, chemotherapy, or their combination) would have a lower response rate. Finally, the investigation of demographic characteristics and externalizing psychopathology as potential predictors of MPH response was exploratory given inconsistent findings in the ADHD literature. We were unable to investigate the predictive value of internalizing pathology given patients were excluded from the MPH trial for these diagnoses.