Major depression is the most common psychiatric disorder among cancer patients and is associated with decreased quality of life, significant deterioration in recreational and physical activities, relationship difficulties, sleep problems, more rapidly progressing cancer symptoms, and more metastasis and pain relative to nondepressed cancer patients. Although some research has explored the utility of psychological interventions with cancer patients, only one study to date has explored the potential benefits of cognitive-behavior therapy among cancer patients with well-diagnosed depression. Addressing this gap in the literature, this study represents an open clinical trial to assess the effectiveness of a brief Cognitive-Behavioral Treatment for Depression (CBTD) among depressed cancer patients in a medical care setting. Results revealed strong treatment integrity, good patient compliance, excellent patient satisfaction with the CBTD protocol, and significant pre-post treatment gains across a breadth of outcome measures assessing depression, anxiety, quality of life, and medical outcomes. These gains also were associated with strong effect sizes and generally maintained at 3-month follow-up. Behavioral activation interventions, especially when paired with cognitive techniques, may represent a practical medical care treatment that may improve psychological outcomes and quality of life among cancer patients. Study limitations and future research directions are discussed.