We compared biweekly irinotecan plus cisplatin (BIRIP) with irinotecan alone as the second-line chemotherapy (SLC) for advanced gastric cancer (AGC).Patients with metastatic or recurrent gastric cancer refractory to S-1-based first-line chemotherapy were randomly assigned to receive BIRIP (irinotecan 60mg/m 2 plus cisplatin 30mg/m 2 , every 2weeks) or irinotecan alone (irinotecan 150mg/m 2 , every 2weeks). The primary end-point was to show the superiority of BIRIP to irinotecan in terms of progression free survival (PFS).130 patients were enrolled. PFS was significantly longer in the BIRIP group (3.8months [95% confidence interval (CI) 3.0–4.7]) than in the irinotecan group (2.8months [2.1–3.3]; hazard ratio 0.68, 95% CI 0.47–0.98; P=0.0398). Median overall survival was 10.7months in the BIRIP group and 10.1months in the irinotecan group (HR 1.00, 95% CI 0.69–1.44, P=0.9823). The objective response rate was 22% in the BIRIP group and 16% in the irinotecan group (P=0.4975). However, the disease control rate was significantly better in the BIRIP group (75%) than in the irinotecan group (54%, P=0.0162). The incidences of grade 3 or worse adverse events did not differ between the two groups. Any grade elevation of serum creatinine was more common in the BIRIP group (25% versus 8%, P=0.009), but any grade diarrhoea (17% versus 42%, P=0.002) was more common in the irinotecan group.BIRIP significantly prolonged PFS as compared with irinotecan alone and was tolerated as SLC, but did not demonstrate the survival benefit in this trial.