An outpatient regimen of interferon-alpha (IFN-alpha), interleukin-2 (IL-2) and 5-fluorouracil (5-FU) was previously reported to have significant activity (response rate 48.6%) in patients with advanced renal cell carcinoma (RCC). The patient group reported were generally of good performance status (PS), had undergone previous nephrectomy and would be considered of good prognosis with respect to response and survival after treatment with IL-2. The characteristics of patients with RCC referred to specialist units in the UK differ from that patient group in that many patients present with metastatic disease, are of poor PS and are considered unfit for nephrectomy. We tested the three drug regimen in a representative patient group of 55 patients who had: median PS of 1 (range 0-2); median time from diagnosis to treatment of 2.7 months (0.2-113); and median number of sites of disease 3 (1-5). 22/55 had not had prior nephrectomy and 31 were considered of poor risk, 15 moderate risk and only 9 of good risk. Treatment consisted of an 8 week cycle of IFN-alpha 6 MU/m2 day 1 weeks 1 and 4 and thrice weekly weeks 2-3 and 9 MU/m2 thrice weekly, weeks 5-8. IL-2 20 MU/m2 days 3-5, weeks 1 and 4 and 5 MU/m2 thrice weekly weeks 2-3. 5-FU 750 mg/m2 day 1 of weeks 5-8. There were no complete responses (CR), 9 (17%) partial responses (PR) and 13 patients (24%) had stable disease. Sixteen patients withdrew early from treatment and were not evaluable for response. Amongst 25 evaluable patients who had undergone nephrectomy the response rate was 32% (95% CI: 14-50%). Only 1 response was seen in patients who had not undergone nephrectomy. Survival was predicted by PS, nephrectomy, number of sites of metastasis and risk group. Most patients experienced significant toxicity of grade I/II but few grade III/IV toxicities were seen as compared to intravenous IL-2 regimens. These data are part of a large data set that has been submitted for publication in The British Journal of Urology. The regimen has been shown to have activity but this is seen predominantly in patients of good PS, with prior nephrectomy and limited sites of disease. Patients of poor risk are likely to experience significant toxicity without benefit and should be offered alternative palliative therapies.