Objective: In this Phase II trial, we evaluated a novel psychological treatment for depressed patients coping with the stresses of cancer. Effectiveness of a combined biobehavioral intervention (BBI) and cognitive behavior therapy (CBT) was studied. Method: Participants were 36 cancer survivors (mean age = 49 years; 88% Caucasian; 92% female) diagnosed with major depressive disorder. A single group pre-post design was used. Treatment consisted of up to 20 individual 75-min combined BBI/CBT sessions. Outcomes were change in interviewer (Hamilton Rating Scale for Depression; Williams, 1988) and self-rated depressive symptoms (Beck Depression Inventory-Second Edition; Beck, Steer, & Brown, 1996) as well as change in cancer relevant symptoms (Fatigue Symptom Inventory [Hann et al., 1998] and Brief Pain Questionnaire [Daut, Cleeland, & Flanery, 1983]) and quality of life (Medical Outcomes Study Short Form-36; Ware et al., 1995). Mixed-effects modeling, a reliability change index, and generalized linear models were used. All analyses were intent-to-treat. Results: Depressive symptoms significantly improved. In addition, 19 of 21 study completers met criteria for remission. Significant improvements were also noted in fatigue and mental health quality of life. Both concurrent anxiety disorders and high levels of cancer stress (Impact of Events Scale; Horowitz, Wilner, & Alvarez, 1979) were each associated with beginning and concluding treatment with greater depressive symptoms. Conclusions: CBT components were successfully incorporated into a previously efficacious intervention for reducing cancer stress. The BBI/CBT intervention warrants further research in evaluating its efficacy compared with well-established treatments for depression. (Contains 2 figures and 4 tables.)