Background: Although adjuvant chemotherapy improvs the survival rate of stage III gastric cancer after curative D2 gastrectomy, the overall benefit is unsatisfactory. Therefore, the study was designed to evaluate the efficacy and safety of adjuvant nab-paclitaxel plus S-1 (AS) versus oxaliplatin plus capecitabine (CAPOX) in the treatment of stage III gastric adenocarcinoma (GAC) after curative D2 gastrectomy. Methods: This phase 3, open-label, randomized study was conducted in patients with stage III GAC after curative D2 gastrectomy. Patients were randomized (1:1) to receive adjuvant AS (100 mg/m² nab-paclitaxel on days 1 and 8; 40-60 mg oral S-1 twice daily on days 1-14) or CAPOX (130 mg/m² oxaliplatin on day 1; 1000 mg/m² oral capecitabine twice daily on days 1-14), repeat every 3 weeks for 8 cycles. The primary endpoint was the 3-year disease-free survival (DFS) rate by intention-to-treat analysis. Secondary endpoints included overall survival (OS) and safety. Results: Between March 2020 and August 2022, 280 patients were screened and 233 were randomly assigned to study treatment (AS, 115; CAPOX, 118). The median age was 62 years (range, 27-77) in AS and 63 years (range, 35-75) in CAPOX. The pathological stages were 42.61% stage IIIA, 34.78% stage IIIB, and 22.61% stage IIIC in AS, while those of CAPOX were 47.46% stage IIIA, 30.51% stage IIIB, and 22.03% stage IIIC. The 1-year DFS rate was 89.0% in AS versus 76.9% in CAPOX. The 1-year OS rate was higher in AS versus CAPOX (100% vs. 95.5%). Seven (6.09%) in AS and 11 (9.32%) in CAPOX experienced recurrence during follow-up; thereinto, one in CAPOX confirmed recurrence with tumor markers and clinical manifestations. Recurrence sites in AS and CAPOX involved the peritoneum (1 vs. 4), locoregional (1 vs. 2), and distant (5 vs. 6), of which, certain patients had 2 simultaneously. Among 6 deaths in CAPOX, 3 died from GAC, 1 died from other diseases and 2 died from unknown. The median relative dose intensity was 96.91% for nab-paclitaxel and 88.00% for S-1 in AS, 82.77% for oxaliplatin and 79.36% for capecitabine in CAPOX. Certain patients in AS (38.26%) and CAPOX (22.03%) experienced grade 3/4 adverse events (AEs). The most common AEs in AS and CAPOX included anemia (20.96% vs. 19.63%), neutropenia (30.70% vs. 21.02%), and thrombocytopenia (1.10% vs. 15.47%). Conclusions: In this study, AS showed longer trends in the DFS rate, OS rate, and manageable safety profile in patients with stage III GAC after curative D2 gastrectomy compared with CAPOX, suggesting a potential therapeutic option for this population. Clinical trial information: NCT04135781.