Background A 4-week administration of tegafur/gimeracil/oteracil (S-1) followed by a 2-week rest is the standard adjuvant chemotherapy for surgically resected advanced gastric cancer. This study aimed to evaluate the oncological feasibility of a 2-week S-1 administration followed by a 1-week rest, which is frequently applied in clinical practice to reduce toxicity and improve drug adherence. Methods We retrospectively enrolled patients with stage II/III gastric cancer who received S-1 adjuvant chemotherapy following radical gastrectomy from 2006 to 2016 in three institutions. Two-week and 4-week regimen cohorts were compared for relative dose intensity (RDI) as a primary outcome, and treatment completion rate, adverse event incidence, overall survival (OS), and relapse-free survival (RFS) as secondary outcomes. Confounders were adjusted for using propensity score matching (PSM). Results One hundred and thirty-four patients received the 2-week regimen and 121 patients received the 4-week regimen. Ninety-five patients were extracted from each group after PSM. The RDIs of S-1 in the 2-week and 4-week cohorts were 73.5 and 69.9%, respectively (p = 0.35), which were not significantly di