The impact of systemic therapy on survival of patients with metastatic melanoma is uncertain. This retrospective analysis aimed to compare the response rates and survival of patients without prior therapy with cisplatin, vinblastine, dacarbazine and interleukin (IL)-2 who were treated with biochemotherapy (containing these drugs plus interferon-alpha) with those of patients who received combination chemotherapy with and without interferon-alpha (chemotherapy +/- IFN). Records for 616 chemo-naive patients with unresectable metastatic melanoma who were treated on eight Phase II/III clinical trials between 1987 and 2001 were combined and reviewed The database included patients with melanoma of the skin (497 cases), unknown primary melanoma (83 cases), mucosal melanoma (21 cases), and uveal melanoma (15 cases). Two hundred sixty-four patients received biochemotherapy, and 352 received chemotherapy +/- IFN. The overall response rate (complete and partial) of patients treated with biochemotherapy was 52% (138/264) compared with 35% (122/352) among patients treated with chemotherapy +/- IFN regimens. The median survival times for patients in the biochemotherapy and chemotherapy +/- IFN groups were 12.2 mo (95% CI: 10.9, 13.5) and 9.1 mo (95% CI: 8.1, 10.4), respectively (p < 0.0001). Five-year overall survival rates of patients treated with biochemotherapy and chemotherapy +/- IFN were 17% and 7% (p = 0.0004), respectively. Ten-year overall survival rates were 15% and 5% (p = 0.0001), respectively. We conclude from these studies that patients benefited more from biochemotherapy than other regimens.