The objective of this study was to report our experience with 38 consecutive patients with metastatic melanoma treated with high-dose (HD) bolus interleukin (IL)-2 after disease progression on or after biochemotherapy as the only earlier treatment for metastatic disease. We conducted a retrospective review of all patients with metastatic melanoma treated with HD IL-2 at the Oncology Center of Hospital Sirio-Libanes between October 2000 and December 2009. The treatment consisted of IL-2, of 600,000 U/kg every 8 h for up to 14 doses, followed by 1-week rest and readmission for the second cycle. Responders received up to four additional cycles. Median follow-up was 9 months. The overall response rate was 23.6%, and we found no correlation between earlier response to biochemotherapy and response to HD IL-2. The median survival was 9.5 months for all patients and 36.1 months for the responders. The most frequent grade 3 or 4 adverse events were hypotension, diarrhea, and respiratory distress, and one patient died from septic shock. We concluded that HD IL-2 has clinically meaningful antitumor activity in patients with metastatic melanoma whose disease has progressed after biochemotherapy. This is a treatment alternative in patients with no central nervous system involvement and who are fit enough to tolerate it, regardless of the initial response to biochemotherapy.