Background: The standard of care for locally advanced gastric cancer in Asia is still upfront gastrectomy with D2 lymph node dissection followed by adjuvant chemotherapy (AC). Both capecitabine plus oxaliplatin (CAPOX) and S-1 are accepted. Which of the two types of chemotherapy is better is still controversial. Methods: For this retrospective nationwide cohort study, data were obtained from the NHIS of Korea. As the NHIS is a single-payer healthcare system, it covers the entire population in the Republic of Korea and it also provides comprehensive information which contains demographic data, healthcare utilization, pharmaceutical prescriptions, and death for each patient. In study population, we included patients who received gastrectomy with a primary diagnosis of gastric cancer which were certified by international classification of disease (ICD) 10th codes of C16.x from January 1st 2013 to December 31th 2018. Survival outcomes of patients who received postoperative chemotherapy were compared based on S-1 (Arm S) vs. CAPOX (Arm C) as well as other relevant clinical variables such as age, sex, co-morbidity and completion of planned treatment. Results: During the study period, 98,556 patients were identified to have undergone both gastric cancer and surgery. After excluding ineligible subjects, a total of 6,602 patients were included in the analysis. Of these, there were 4,199 in Arm S and 2,403 in Arm C, respectively. After propensity score matching, final study population were identified 2,067 in each arm. Arm C showed statistically inferior survival (OS) compared to Arm S (5-year OS rate, 84.0% vs 90.0%, p < 0.0001). Disease-free survival (DFS) was also shorter in Arm C than Arm S (5-year DFS, 78.4% vs 86.1%, p < 0.0001). Age (65 ≥ vs. < 65) and incompleteness of the planned treatment had also significant negative effect on both OS and DFS. Charlson co-morbidity index (≥4 vs. 0-3) was not associated with the difference of OS or DFS. After adjusting with multivariable analysis, Arm C still showed worse OS (HR 1.609, 95% CI, 1.339-1.934, p < 0.0001) and DFS (HR 1.552, 95% CI, 1.333-1.807, p < 0.0001) compared to Arm S. Conclusions: Both S-1 and CAPOX showed excellent efficacy. This nation-wide cohort study suggests that S-1 can be a better option in some clinical situations.