Several phase II trials have shown that gemcitabine and fluoropyrimidines have marginal but definite activity in patients with metastatic renal cell cancer (mRCC). We retrospectively analyzed the 193 mRCC patients consecutively seen in our institutions during the last 11 years, of whom 39 were treated with chemotherapy (CT): 16 were treated with CT alone (gemcitabine and 5-fluorouracil) and 23 with the same regimen plus low dose of interleukin-2 and interferon-alpha. The main end point of the analysis was to estimate response rate and time to progression (TTP); the secondary end point was to evaluate overall survival (OS) and toxicity. Overall TTP was 3.2 months (95% confidence interval: 2.22-4.18). Three patients (7.7%) achieved a partial response and 10 (25.6%) stable disease. Median OS was 9.23 months (95% confidence interval: 7.16-11.31) and the 1-year survival rate was 40.6%. Although not statistically significant, the response and disease control rates were better in the pretreated patients (8% vs. 7% and 44% vs. 14%), with a favorable trend for TTP and OS (4.9 vs. 3.2 mo and 12.9 vs. 4.2 mo). Grade 3 to 4 toxicities included hematologic toxicity and depressed mood. OS was strongly influenced by performance status, the presence of brain metastasis, and response after 3 cycles of therapy. In these mRCC patients, both CT and chemoimmunotherapy showed modest but definite activity and a regimen CT-based should be offered to patients with progressive mRCC. The association of these treatments with antiangiogenetic agents should be tested in future trials.