Background: Adjuvant therapy for stage II and III advanced gastric cancer (AGC) is essential in improving patient outcomes. The standard therapy, TS-1 at 80 mg/m²/day for 4 weeks with a 2-week rest, is recommended for 1 year or 8 courses. This study investigates the efficacy and safety of a 3-weekly adjuvant TS-1 regimen in AGC patients. Methods: We conducted an analysis of 93 patients who underwent gastrectomy with D2 lymphadenectomy and initiated a 3-weekly adjuvant TS-1 regimen between February 2017 and May 2022. The novel regimen consisted of TS-1 at 80 mg/m2/day for 2 weeks, followed by a 1-week rest, with a treatment goal of 1 year or 16 courses. Results: Among the 93 patients, 12 (13%) experienced disease recurrence during a median follow-up of 24.6 months (range: 4.2 to 63.3 months). Of the Stage II patients (n=73), 7 cases (9.5%) had recurrent disease, while 5 cases (25%) in the Stage III group (n=20) experienced recurrence. Recurrence-Free Survival (RFS) rates at 1 year, 3 years, and 5 years were 92.0% (95%CI 86.5 to 97.9), 84.7% (95%CI,76.4% to 93.9%), and 78.6% (95%CI, 65.8% to 94.0%), respectively. A total of 80 patients (86%) completed the adjuvant 3-weekly TS-1 treatment for 1 year or 16 courses, while 25 patients (26.9%) completed the treatment with dose reductions. Adverse events, primarily Grade 1 or 2 diarrhea (28%) and nausea (20%), were manageable. Conclusions: The novel 3-weekly TS-1 regimen as adjuvant therapy exhibited favorable efficacy and tolerable toxicity in AGC patients. These findings suggest the need for further investigation of this regimen in future clinical studies.