Background: The beneficial and deleterious effects of Helicobacter pylori (H. pylori) infection remain to be fully elucidated. A clear understanding of the infectious mechanism is crucial since the potential effect may result in a survival benefit for life-threatening diseases. To understand the potential beneficial effect in advanced gastric cancer, we analyzed survival for patients treated with surgery-only or adjuvant chemotherapy on the basis of H. pylori infection status. Methods: A cohort of 491 patients who underwent R0 resection for locally-advanced gastric cancer between 2000 and 2009 at 12 institutions in northern Japan from the Northern Japan Gastric Cancer Consortium was included. H. pylori infection status was assessed from paraffin-embedded formalin-fixed samples. Overall survival (OS) and disease-free survival (DFS) in surgery-only (Surgery) and adjuvant chemotherapy (S-1) groups were analyzed. A propensity score matching was employed to correct for confounding factors by indication. To evaluate the local immune response from the immune-evasion status of the tumor, immunostaining of Programmed Death-Ligand 1 (PD-L1) protein was performed with PharmDx antibody clone 22C3. Results:H. pylori infection was positive in 175 patients and negative in 316 patients. H. pylori-positive patients showed significantly better survival than H. pylori-negative patients in both OS [hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.42-0.84; p = 0.003)] and DFS (HR 0.68, 95% CI 0.49-0.94; p = 0.018). There were no significant interactions between H. pylori infection status and the clinicopathological background except for S-1 doses in DFS (p = 0.0482). Propensity score matching further confirmed that S-1 was virtually only effective when tumors were H. pylori-positive. The PD-L1 protein expression pattern suggests that H. pylori-positive status confers an advantage that might suppress immune-evasion of tumor cells. Conclusions: The favorable outcome of H. pylori-positive patients suggests that the host immune system is modulated by H. pylori enhancing post-operative chemotherapeutic efficacy (NCT01905969).