The American Cancer Society estimates that 11.1 million Americans were living with cancer in 2005, and that 1.5 million new cases of cancer were diagnosed in 2009 (American Cancer Society, 2009). Because of the debilitating nature of advanced cancers and their treatment, many persons with advanced cancer require the assistance of an informal caregiver, defined as an unpaid individual who assists someone else who has functional impairment with activities of their daily living (Scott, 2006). Over 22 million Americans (with estimates running as high as 52 million) are involved in informal caregiving (Scott, 2006), and a nationally representative survey of older Americans revealed that end-of-life caregivers provide an average of 43 hours of assistance per week (Wolff, Dy, Frick, & Kasper, 2007). Unfortunately, there is substantial evidence documenting deleterious caregiver physical and mental health effects, often referred to as caregiver burden. As people live longer with cancer, the negative effects of caregiver burden will only continue to grow. A meta-analysis of 84 caregiver burden studies across all types of chronic disease showed that caregivers exhibit higher levels of stress and depression, lower subjective well-being, and worse physical health compared to non-caregiver controls (Pinquart & Sorenson, 2003a). Caregiver burden has also been identified as an independent risk factor for mortality: controlling for demographics and co-morbid disease, caregivers were 63% more likely to die within a 4-year span than non-caregiver controls (Schulz & Beach, 1999). Although the negative effects of caregiving are most pronounced in caregivers of patients with dementia, informal caregivers of patients with cancer also report worse mental health (Ringdal et al., 2004; Braun, Mikulincer, Rydall, Walsh, & Rodin, 2007; Janda et al., 2007; Rhee et al., 2008). In addition, caring for someone with a slow-developing cancer, such as colon or lung cancer, has been shown to increase 9-year mortality rates versus caregivers of patients with ‘quick’ cancers (Elwert & Christakis, 2008). Even hospitalization for cancer may increase the risk of spouse mortality within 1 year (Christakis & Allison, 2006). The evidence seems clear that informal caregiving can exact a heavy toll. Because of the significant effect of caregiving on health outcomes, various interventions to alleviate caregiver burden have been tested, but these have produced equivocal results (Harding & Higginson, 2003). A meta-analysis of 78 caregiver interventions across a wide array of chronic ailments found only marginal effects (0.14 < d < 0.41) (Sorenson, Pinquart, & Duberstein, 2002). A review of end-of-life palliative care studies concluded that the evidence for interventions improving outcomes for caregivers of patients with cancer was weak (Lorenz et al., 2008). Psychoeducational interventions that teach caregivers about symptom management, self-care, and coordination of resources have been shown to improve caregivers’ physical health, distress, and depression relative to controls, but these effects appeared short-lived as group differences disappeared shortly after the interventions ceased (McCorkle, Robinson, Nuamah, Lev, & Benoliel, 1998; Jepson, McCorkle, Adler, Nuamah, & Lusk, 1999). Caregiver interventions designed to improve problem-solving and coping skills have been shown to improve physical and social functioning (Toseland, Blanchard, & McCallion, 1995). The benefits of both types of intervention, however, were most evident for those caregivers that entered the study with the highest impairment (Toseland et al., 1995; Jepson et al., 1999). One exception was a problem-solving and coping skills intervention that successfully improved caregiver quality of life and reduced caregiver burden at 30 days post-intervention compared to both a usual care condition and an emotional support intervention (McMillan et al., 2005). Unfortunately, this intervention failed to change the proposed mediators (e.g. problem-focused coping), leaving the mechanism behind this success unknown. In a disheartening statement, a review of interventions for caregivers of patients with cancer concluded that “no intervention can be recommended for nursing practice as an evidence-based strategy to reduce strain and burden in caregivers” (Honea et al., 2008) One explanation for the ineffectiveness of earlier caregiver interventions is that these programs neglected the deteriorating health of caregivers’ loved ones (Hebert, Arnold, & Schulz, 2007). Cancer patients’ physical health (e.g. functional impairment, experience of pain) and quality of life have been found to predict caregiver burden, distress, depression, and quality of life (Miaskowski, Kragness, Dibble, & Wallhagen, 1997; Beach, Schulz, Yee, & Jackson, 2000; Fang, Manne, & Pape, 2001; Harding, Higginson, & Donaldson, 2003; Given et al., 2004). A meta-analysis showed that among couples in which one partner had cancer, each partner’s level of distress was significantly correlated (r = .29) and distress was not significantly different between partners (Hagedoorn, Sanderman, Bolks, Tuinstra, & Coyne, 2008). Additionally, a randomized controlled trial (RCT) of a caregiver intervention found that only a reduction in patient symptoms predicted decreases in caregiver depression (Kozachik et al., 2001). It was argued, therefore, that caregiver interventions will not be effective if the patient is suffering, and that patient-directed interventions might help caregivers indirectly by improving patient outcomes (Hebert et al., 2007). However, previous palliative care interventions for patients with cancer have failed to affect caregiver outcomes despite demonstrating improvements in patients’ quality of life (Clark et al., 2006). For example, a RCT of a psychoeducational intervention produced marked improvements in patient depression and symptom severity in the intervention condition but a non-significant trend that caregivers in the intervention showed higher depression scores than controls (Kurtz, Kurtz, Given, & Given, 2005). This finding indicates that certain interventions may inadvertently result in increased caregiver burden. Even a nursing intervention that increased longevity among patients with cancer only resulted in short-term benefits for caregiver stress and depression (Giarelli, Pisano, & McCorkle, 2000). The ENABLE II (Educate, Nurture, Advise Before Life Ends) palliative care intervention provided a prime opportunity to determine if an effective patient-directed intervention could alleviate caregiver burden. ENABLE II was designed to improve problem-solving skills, symptom management, and communication skills, as well as promote advance care planning (e.g., advanced directives and “do not resuscitate” orders) among patients with advanced cancer. Importantly, participants were recently diagnosed with cancer and the intervention occurred concurrently with cancer treatment, such as chemotherapy and radiation, in an effort to provide elements of palliative care to patients before death was imminent (Bakitas et al., 2009a). In this RCT, the intervention proved effective in improving patients’ quality of life, reducing symptom intensity, and lowering depressed mood compared to a usual care control condition in the 7 months following study enrollment (Bakitas et al., 2009b). Although the intervention did not directly involve caregivers, we hypothesized that the intervention would improve caregiver outcomes indirectly through improvements in patient outcomes (Hebert et al., 2007).