Objective: Major depression is the most common psychiatric disorder among breast cancer patients and is associated with substantial impairment. Although some research has explored the utility of psychotherapy with breast cancer patients, only 2 small trials have investigated the potential benefits of behavior therapy among patients with well-diagnosed depression. Method: In a primarily Caucasian, well-educated sample of women (age = 55.4 years, SD = 11.9) diagnosed with breast cancer and major depression (n = 80), this study was a randomized clinical trial testing the efficacy of 8 sessions of behavioral activation treatment for depression (BATD) compared to problem-solving therapy. Primary outcome measures assessed depression, environmental reward, anxiety, quality of life, social support, and medical outcomes. Results: Across both treatments, results revealed strong treatment integrity, excellent patient satisfaction with treatment protocols, and low patient attrition (19%). Intent-to-treat analyses suggested both treatments were efficacious, with both evidencing significant pre–post treatment gains across all outcome measures. Across both treatments, gains were associated with strong effect sizes, and based on response and remission criteria, a reliable change index, and numbers-needed-to-treat analyses, approximately ¾ of patients exhibited clinically significant improvement. No significant group differences were found at posttreatment. Treatment gains were maintained at 12-month follow-up, with some support for stronger maintenance of gains in the BATD group. Conclusions: BATD and problem-solving interventions represent practical interventions that may improve psychological outcomes and quality of life among depressed breast cancer patients. Study limitations and future research directions are discussed.