OBJECTIVES: To describe the implementation of a collaborative care (CC) screening and treatment program for major depression in people with cancer, found to be effective in clinical trials, into routine outpatient care of a cancer center. METHOD: A mixed-methods observational study guided by the RE-AIM implementation framework using quantitative and qualitative data collected over five years. RESULTS: Program set-up took three years and required more involvement of CC experts than anticipated. Barriers to implementation were uncertainty about whether oncology or psychiatry owned the program and the hospital's organizational complexity. Selecting and training CC team members was a major task. 90% (14,412/16,074) of patients participated in depression screening and 61% (136/224) of those offered treatment attended at least one session. Depression outcomes were similar to trial benchmarks (61%; 78/127 patients had a treatment response). After two years the program obtained long-term funding. Facilitators of implementation were strong trial evidence, effective integration into cancer care and ongoing clinical and managerial support. CONCLUSION: A CC program for major depression, designed for the cancer setting, can be successfully implemented into routine care, but requires time, persistence and involvement of CC experts. Once operating it can be an effective and valued component of medical care.