OBJECTIVE To evaluate the efficacy and toxicity of the alternating administration of natural (n) interferon (IFN)-alpha and recombinant (r) IFN-gamma for metastatic RCC. METHODS The study comprised 24 patients (median age 60 years, range 42-77), 20 of whom were evaluable for response and all 24 evaluable for toxicity. Initially, nIFN-alpha was administered subcutaneously on days 1 and 3, and rIFN-gamma on day 2, for 1-2 weeks in the evening or at night, both at doses of 3 MU. If this regimen was tolerated, nIFN-alpha and rIFN-gamma were administered at the same doses on days 1, 3 and 5, and on days 2 and 4, respectively. RESULTS There were three complete remissions and two partial remissions, giving a total response rate of 25%. All responders (complete plus partial remission) had undergone nephrectomy. Multiple lung metastases completely disappeared from four responders. The median and maximum time to remission in the responders were 2 and 7 months, respectively. The survival time of the responders was significantly longer than that of those not responding (stable and progressive disease, P=0.0202). Toxicities were mostly limited to WHO grades 1 and 2, with grade 3 leucopenia and grade 4 hepatic dysfunction in only one patient each. These toxicities were transient and there were no treatment-related deaths. CONCLUSIONS The alternating administration of nIFN-alpha and rIFN-gamma is an effective treatment for metastatic RCC. This treatment is particularly suitable for patients who have undergone nephrectomy and have lung metastases.