Although 5-fluorouracil remains the mainstay of treatment for advanced gastric cancer (AGC), no standard chemotherapy regimen exists. Combinations of irinotecan with folinic acid and infusional 5-fluorouracil (5-FU) (ILF) have shown good efficacy with acceptable toxicity in patients with metastatic colorectal cancer. At present, only sparse data on ILF are available for AGC. Therefore we conducted a prospective study of this combination in 25 consecutive patients with metastatic gastric cancer. Median age was 63 years, 10 had received prior chemotherapy and 13 presented initially with peritoneal carcinosis. Treatment consisted of irinotecan 80 mg/m2, folinic acid 500 mg/m2 and infusional 5-FU 2.0 g/m2 over 24 h, given weekly for 6 weeks followed by a 1-week rest. Grade 3/4 hematologic toxicity occurred in six patients (anemia = 4, neutropenia = 1 and leukopenia = 1). Non-hematologic toxicity consisted mainly of nausea/vomiting (grade 3/4 in six patients) and diarrhea (grade 3/4 in 10 patients). The overall response rate was 20% for first- and second-line treatment, with two complete and three partial responses. Another nine patients (36%) had stable disease, for a tumor control rate of 56%. Median time to progression was 4 months, median overall survival and survival for patients with tumor control was 7 and 13 months, respectively. We conclude that ILF is a feasible outpatient regimen with manageable toxicity that provides tumor control in a high proportion of patients with advanced gastric cancer, even among those with unfavorable prognostic features.