There continues to be a need to develop better treatment models for alcohol dependence as evidenced by the relatively low rates of access to treatments found in epidemiological studies (Grant et al., 2004). The Institute of Medicine has suggested that intervening for alcohol dependence with pharmacotherapy in the primary care setting or other nonspecialty care settings may be an effective way to address the gap between treatment need and lack of access (Institute of Medicine, 1996, 2005). Currently, there are 3 FDA-approved pharmacotherapies available for the treatment of alcohol dependence—disulfiram, naltrexone (both oral and depot formulations), and acamprosate. Naltrexone, an opioid antagonist, has been used successfully in the treatment of alcohol dependence (e.g., O’Malley et al., 1992 and Volpicelli et al., 1992) and is safe and well tolerated (Croop et al., 1997; O’Malley et al., 1992; Volpicelli et al., 1992). The majority of studies continue to show a greater efficacy of naltrexone over placebo either in the main (Anton et al., 1999; Jaffe et al., 1996; Monterosso et al., 2001; Morris et al., 2001; Volpicelli et al., 1997b) or secondary analysis (Chick et al., 2000; Heinala et al., 2001; Monti et al., 2001; Oslin et al., 1997). Although this evidence for the effectiveness of naltrexone is compelling, a few studies have failed to show the efficacy of naltrexone (Kranzler et al., 2000; Krystal et al., 2001). So far, all clinical intervention research studies except 2 (Latt et al., 2002; O’Malley et al., 2003) have delivered naltrexone for the treatment of alcohol dependence only in the context of a formal psychosocial intervention (CBT, MET, MM, etc). However, many of these interventions require a substantial commitment to specialty training and require multiple visits by the patient. Thus, the effectiveness of naltrexone in the absence of formal psychotherapy has not been well investigated. In addition, there are several types of psychosocial interventions that could be effectively combined with pharmacotherapy. Cognitive-behavioral therapy (CBT) has been shown to be an effective psychosocial treatment for alcohol dependence (Kadden et al., 1995) and has been theorized to be beneficial for enhancing naltrexone effectiveness (Anton et al., 1999; Jaffe et al., 1996; O’Malley et al., 1992). A CBT-based intervention was used for all subjects in a study that showed naltrexone to be superior to placebo (Anton et al., 1999), and group CBT was shown to enhance the effectiveness of naltrexone over group supportive therapy in a study by Heinala et al. (2001). Recently, a 12-week study demonstrated that the combination of naltrexone and CBT was more effective than placebo or motivational enhancement therapy (MET) with or without naltrexone (Anton et al., 2005). It is theorized that this effect may relate to the need for addressing psychosocial issues not specifically dealt with in MET. CBT has specific modules on family conflict, social skills training to deal with high-risk situations, and coping with craving, which are not generally part of MET therapy. However, a larger NIAAA-supported COMBINE study failed to demonstrate an advantage of receiving CBT treatment while taking naltrexone compared to taking naltrexone with Medical Management (MM), a less-intensive therapy (Anton et al., 2006). Less-intensive motivationally based interventions such as MM have been theorized to provide a strong platform in which to deliver pharmacotherapy (Pettinati et al., 2004). The BRENDA model (Volpicelli et al., 1997a) was also designed specifically to be used in combination with pharmacotherapy for alcohol dependence and includes motivational enhancement counseling with a goal of promoting reductions in alcohol use while promoting adherence to treatment. BRENDA served as the psychosocial intervention in a trial that found naltrexone to be superior to placebo (Monterosso et al., 2001), suggesting that it is a viable intervention. Delivered by nurses or other allied health professionals, BRENDA or MM could be used in multiple clinical settings including specialty care or primary care. The BRENDA and MM models are based on MET but includes specific discussions around pharmacotherapy. BRENDA does not include the structure found in CBT and, in particular, does not have modules for family involvement, methods for social skills training, or coping with craving. The aims of this project were to test the main effects of naltrexone/placebo and the main effects of specific psychosocial interventions, including a medication clinic model alone, over the course of 24 weeks of treatment. The medication clinic model was included to mimic clinical practice typically seen in nonspecialty settings such as primary care. This model of care is common in the treatment of depression. The CBT condition was included as the “gold standard” treatment with proven efficacy in the treatment for addiction. We hypothesized moderate-to-large treatment effects favoring naltrexone as well as between the 3 psychosocial intervention groups, with CBT and BRENDA hypothesized to be better than the medication clinic model. The sample size (240 subjects) was sufficient to demonstrate at least moderate differences in the main effects assuming 80% or better treatment adherence over the 24 weeks. The original hypothesis also included a testing of the interaction between psychosocial intervention and medication; however, the sample size would only be sufficient for very large interaction effects. The focus on 24 weeks of treatment was based on reports of several post-treatment follow-up results (Anton et al., 1999; Monti et al., 2001; O’Malley et al., 1996), which suggested that discontinuing naltrexone after 3 months leads to a gradual return to heavy alcohol use, and that longer durations of naltrexone administration might be useful.