Purpose: The objective of this study was to determine the tolerance and effect of moderate-dose recombinant human interleukin-2 (rHu IL-2) and tumor- infiltrating lymphocytes (TIL) in patients with metastatic melanoma (MM) or renal cell carcinoma (RCC) refractory to standard therapy. Patients and Methods: Twenty-six patients (18 MM and eight RCC) were entered onto this pilot study. TIL were isolated from fresh biopsy material and activated with anti-CD3 antibody, OKT3, for 48 hours and expanded in 100 IU/mL r-methionyl Hu IL-2 alanine 125 (r-met Hu IL-2 [ala-125]). At least 1010 TIL were reinfused intravenously in three divided injections on days 2, 4, and 6 of the protocol. A maximum dose of 30,000 U/kg of IL-2 per injection was administered every 8 hours from day 2 through day 11 for a total of 28 doses. Results: Sixteen melanoma patients completed the study. Of these, three (19%) showed a durable complete response (CR), nine (56%) had no response (NR), and four (25%) had progressive disease (PD). One nonresponder demonstrated complete tumor regression within 1 year of treatment. Of four assessable RCC patients, two experienced a minor response (MR) and two showed NR. All TIL cultures showed comparably high cytotoxic activity as determined by antibody- redirected lysis (ARL). More importantly, melanoma TIL from responders possessed significantly higher cytotoxicity against autologous tumor cells than TIL from nonresponders (P < .05). Production of granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon gamma (IFN-γ), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and IL-4 was similar for TIL from melanoma responders and nonresponders, or TIL from RCC patients. Conclusion: Immunotherapy with polyclonally activated TIL and moderate-dose IL-2 could be successfully used for the treatment of immunogenic tumors with less toxicity end lower costs as compared with high-dose IL-2 protocols.