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AIM To evaluate the efficacy and safety of third-line chemotherapy (CTx) for patients with unresectable or recurrent gastric cancer (GC) refractory to S-1 with or without platinum and taxanes. PATIENTS AND METHODS We retrospectively analyzed clinicopathological and survival data of 26 patients who underwent third-line CTx. RESULTS Irinotecan therapy (odds ratio=0.12, 95% confidence interval=0.02-0.38; p less then 0.01) and ≥2 cycles of third-line CTx (odds ratio=0.01, 95% confidence intervaI=0.01-0.11; p less then 0.01) were independen