In this study the characteristics of the cytotoxic function in a series of patients with metastatic renal cell carcinoma (RCC) were analyzed and the possibility of modulating this capacity in vitro with the use of biologic response modifiers (BMR) such as alpha-interferon (alpha-IFN) and recombinant interleukin-2 (rIL-2) was verified, with the ultimate goal of providing a rationale for a therapeutic approach to this disease with these molecules. Peripheral blood mononuclear cells (PBMC) of patients with advanced RCC were tested for natural killer (NK) and lymphokine-activated killer (LAK) activity both before and after alpha-IFN therapy. In addition, surface markers of unstimulated and stimulated cells were analyzed and in vitro assays were performed to determine the proliferative capacity in response to the stimulus with rIL-2. During an evaluation before treatment, defective NK activity was observed that could be corrected by incubating the cells with rIL-2. In these subjects, LAK cells could be consistently generated after PBMC were activated with this cytokine in vitro. No changes in NK and LAK activity were found after alpha-IFN therapy. In contrast, treatment with alpha-IFN affected the proliferative response of PBMC to rIL-2, and a significant decrease in this in vitro capacity was observed during follow-up. The ability to restore NK activity and obtain an adequate LAK cytotoxicity from the PBMC of patients with RCC supports a therapeutic approach with BRM. However, the fact that this type of treatment affects the proliferative response of PBMC to rIL-2 must be considered when clinical trials are designed for patients with RCC.