Optimal second-line chemotherapy may contribute to favorable survival in patients who receive first-line treatment for advanced gastric cancer. The aim of this retrospective study was to compare a second-line setting using irinotecan with paclitaxel in terms of survival benefit and safety. A total of 179 patients with recurrent or unresectable gastric cancer who had received prior chemotherapy with a fluoropyrimidine-based regimen were treated with irinotecan alone at 150 mg/m(2) on days 1 and 15 every 4 weeks (Cohort I) or weekly paclitaxel at 80 mg/m(2) on days 1, 8 and 15 every 4 weeks (Cohort P) between April, 2004 and March, 2009. Patient characteristics, overall response rate, disease control rate, progression-free survival, overall survival and safety were investigated. Of the 179 patients, 92 received irinotecan and 87 patients who were contraindicated for irinotecan received weekly paclitaxel. The overall response and disease control rates in Cohort I were 6.5 and 43.5%, respectively, as compared with 9.8 and 54.9%, respectively, in Cohort P. No variation was noted in median progression-free survival (Cohort I vs. P, 2.6 vs. 2.8 months; P=0.812), whereas median overall survival (Cohort I vs. P, 9.8 vs. 4.9 months; P<0.0001) differed significantly between the two cohorts. The most common grade 3/4 adverse events were neutropenia, leukopenia, anemia and anorexia, which were tolerable in each treatment cohort. Availability of irinotecan in a second-line setting confers a survival benefit to advanced gastric cancer patients in whom fluoropyrimidine-based first-line chemotherapy was unsuccessful.