We evaluated 567 patients with metastatic melanoma who were treated with high-dose intravenous interleukin-2 (IL-2) to determine whether prior treatment with either alpha-interferon or low-dose IL-2 altered the rates of response to subsequent high-dose IL-2. Of the 567 patients treated, 46 patients had received low-dose IL-2 before, and 78 had received alpha-interferon before. The response rate for patients who had received IL-2 before compared with IL-2 naïve patients was 15% versus 21% respectively (p = 0.39). The response rate for patients who had received alpha-interferon before compared with patients who had not was 13% versus 21% (p = 0.084). Therefore, prior low-dose IL-2 therapy does not appear to prevent a subsequent response to high-dose IL-2. There is a trend for patients who received alpha-interferon before to have a lower-response rate to subsequent high-dose IL-2, but the number of patients evaluated in this study is too small to definitively answer this question.