To determine the effect of human lymphoblastoid interferon (HLBI) on metastatic renal cell carcinoma (MRCC), we performed two clinical trials. First, between 1982 and 1984, we performed a phase II study using 3 mega-units (MU) of HLBI daily in 25 eligible patients with MRCC. Six patients (24.0%) showed objective responses, including 2 with complete response (CR) and 4 with partial response (PR). Patients with a prior nephrectomy or with a good performance status were likely to respond to the therapy. Based on the above observation, we performed a prospective randomized trial to compare 2 different doses of HLBI following nephrectomy. Treatment consisted of HLBI, 3 MU intramuscularly 6 days a week in arm A and 1 MU intramuscularly 6 days a week in arm B. Treatments were started within 4 weeks after the nephrectomy and patients were evaluated every week for 1 month, and every month thereafter. Between 1985 and 1991, 16 patients were enrolled in arm A and 15 patients in arm B. Responses were seen in 5 (31.3%) of the 16 arm A patients (4 CRs and 1 PR) and 3 (20.0%) of the 15 arm B patients (1 CR and 2 PRs). Most responses occurred in patients with lung metastasis and favorable PS. There was no statistical difference in efficacy between the two arms. Hematologic toxicity was more frequent in arm A (43.8%) than arm B (13.3%). We conclude that further studies are needed to secure the clinical efficacy of HLBI for MRCC.