OBJECTIVE The activation of angiogenesis has been proven to suppress the anti-cancer immunity. The evidence of abnormally high pretreatment blood levels of vascular endothelial growth factor (VEGF), which is the main angiogenic factor, has appeared to predict resistance to IL-2 immunotherapy of metastatic renal cell carcinoma (RCC). Therefore, the control of VEGF secretion could influence the efficacy of IL-2. Recent data suggest that erythropoietin (EPO) may modulate VEGF secretion and IL-2 biological activity. On this basis, a study was planned with subcutaneous (s.c.) low-dose IL-2 plus EPO in metastatic RCC, which had progressed on IL-2 alone (6 million IU/day for 6 days/week for 4 weeks). METHODS Patients received IL-2 at the same dose as the previous cycle, plus EPO (10,000 3 times/week until the end of IL-2 therapy. Serum levels of VEGF were measured by enzyme immunoassay on venous blood samples collected at weekly intervals. The study included 12 evaluable metastatic RCC patients. RESULTS The treatment was well-tolerated and most patients referred a relief of IL-2-induced asthenia. A partial response (PR) and 4 stable diseases (SD) were achieved on IL-2 plus EPO, whereas the other 7 patients had a progressive disease (PD). Hemoglobin mean levels were significantly higher on IL-2 plus EPO than during the previous therapy with IL-2 alone in the same patients. In the same way, mean lymphocyte increase was higher on IL-2 plus EPO than on IL-2 alone, even though this difference was not significant. Finally, VEGF increase was significantly lower on IL-2 plus EPO than during IL-2 alone. CONCLUSION This preliminary study shows that the concomitant administration of EPO may allow a control of the neoplastic growth in advanced cancer patients progressing on IL-2 alone, reduce the subjective toxicity, prevent hemoglobin decrease and counteract IL-2-related VEGF increase.