BackgroundWe investigated the feasibility of perioperative chemotherapy with S-1 and leucovorin (TAS-118) plus oxaliplatin in patients with locally advanced gastric cancer.MethodsPatients with clinical T3–4N1–3M0 gastric cancer received four courses of TAS-118 (40–60 mg/body, orally, twice daily for seven days) plus oxaliplatin (85 mg/m2, intravenously, day one) every two weeks preoperatively followed by gastrectomy with D2 lymphadenectomy, followed by postoperative chemotherapy with either 12 courses of TAS-118 monotherapy (Step 1) or eight courses of TAS-118 plus oxaliplatin (Step 2). The primary endpoints were completion rates of preoperative chemotherapy with TAS-118 plus oxaliplatin and postoperative chemotherapy with TAS-118 monotherapy (Step 1) or TAS-118 plus oxaliplatin (Step 2).ResultsAmong 45 patients enrolled, the preoperative chemotherapy completion rate was 88.9% (90% CI 78.0–95.5). Major grade ≥ 3 adverse events (AEs) were diarrhoea (17.8%) and neutropenia (8.9%). The R0 resection rate was 95.6% (90% CI 86.7–99.2). Complete pathological response was achieved in 6 patients (13.3%). Dose-limiting toxicity was not observed in 31 patients receiving postoperative chemotherapy (Step 1, n = 11; Step 2, n = 20), and completion rates were 90.9% (95% CI 63.6–99.5) for Step 1 and 80.0% (95% CI 59.9–92.9) for Step 2. No more than 10% of grade ≥ 3 AEs were observed in  patients receiving Step 1. Hypokalaemia and neutropenia occurred in 3 and 2 patients, respectively, receiving Step 2. The 3-year recurrence-free and overall survival rates were 66.7% (95% CI 50.9–78.4) and 84.4% (95% CI 70.1–92.3), respectively.ConclusionsPerioperative chemotherapy with TAS-118 plus oxaliplatin with D2 gastrectomy is feasible.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10120-023-01388-z.