PURPOSE: The purpose of this study was to examine the pattern of relapse and the treatment of relapse with either surgery or repeat immunotherapy in patients with metastatic melanoma or renal cell carcinoma who had previously responded to interleukin-2-based therapy. PATIENTS AND METHODS: Over a 10-year period 1051 patients with metastatic melanoma or renal cell carcinoma were treated with interleukin-2-based immunotherapy at a single institution. One hundred fifty-nine patients who relapsed after an initial partial response or complete response to interleukin-2-based immunotherapy formed the study population for this retrospective review. Medical records, physical examination forms, and relevant radiographs were reviewed to determine response, relapse site(s), and response to treatment for relapse. RESULTS: Relapse after an initial response to interleukin-2-based therapy occurred in 84 (80%) of 105 patients with metastatic melanoma and in 75 (70%) of 107 patients with metastatic renal cell carcinoma. Relapse after an initial partial response involved 71 (97%) of 73 patients with metastatic melanoma and 55 (86%) of 64 patients with metastatic renal cell carcinoma. The initial site(s) of relapse after a partial response involved a new site(s), old site(s), or both old and new sites with relatively even distribution. Relapse after an initial complete response occurred in 13 (41%) of 32 patients with metastatic melanoma and in 20 (47%) of 43 completely responding patients with metastatic renal cell carcinoma. Surprisingly, the initial site of relapse after a complete response involved only new sites of disease in 70% of patients. Retreatment of relapses with the same interleukin-2-based therapy originally used was effective in only one (2%) of 54 selected patients, but a different interleukin-2-based therapy in 35 patients resulted in five responders (a 14% secondary response rate). Most re-responders, however, responded to treatment with tumor-infiltrating lymphocytes and interleukin-2, and only one of 20 patients responded to retreatment with interleukin-2 alone. Surgical metastasectomy with therapeutic intent in 25 selected melanoma patients and in 31 selected renal cell cancer patients resulted in a 2-year progression-free survival of 18% in patients with metastatic melanoma and 37% in patients with metastatic renal cell carcinoma. DISCUSSION: In patients with metastatic melanoma or renal cell carcinoma, tumor relapse was common after a partial response to an interleukin-2-based therapy and included previously identified sites of disease in most patients. Relapse after a complete response was less frequent and involved only new sites in a majority of patients. In selected patients who relapsed, repeat treatment with the same interleukin-2-based therapy that provided the initial response was rarely effective. However, with a different interleukin-2-based therapy, usually using tumor-infiltrating lymphocytes, repeat treatment induced secondary responses in some patients. In addition, salvage metastasectomy resulted in durable progression-free survival in selected patients.