Background: Multiple clinical studies have shown that adjuvant chemotherapy could prolong the survival of patients after radical resection, it is necessary to explore better treatment options for patients with stage III gastric adenocarcinoma (GAC). We designed this study to evaluate the efficacy and safety of adjuvant nab-paclitaxel combined with S-1 (AS) versus capecitabine combined with oxaliplatin (CAPOX) in GAC. Methods: Patients with stage III GAC after D2 radical resection and achieved R0 resection were randomized 1:1 to receive adjuvant AS (nab-paclitaxel: 100 mg/m², d1 and 8, q3w; S-1: 40-60 mg, bid, d1-14, q3w) or CAPOX (oxaliplatin: 130 mg/m², d1, q3w; capecitabine: 1000 mg/m², bid, d1-14, q3w) for 8 cycles. Stratification analysis was performed according to histological type (differentiated vs undifferentiated GAC) and AJCC 8^th pathological staging (ⅢA vs ⅢB and ⅢC). The primary endpoint was 3-year disease-free survival (DFS) rate, secondary endpoints were overall survival (OS) and safety. Results: Between March 20, 2020 and January 17, 2023, 313 patients were randomized to receive AS (n = 156) or CAPOX (n = 157). Baseline characteristics were generally balanced between the two groups. Median follow-up time was 5.16 months. The 1-year DFS rates were 87.14% and 70.16%, in the AS and CAPOX groups, respectively. The median DFS and 3-year DFS rates were not reached. The 1-year OS rate was 88.47% in AS group, and 63.89% in CAPOX group. At date cutoff, 12 patients (peritoneal recurrence, 1 patient; locoregional recurrence, 3 patients; distant recurrence, 8 patients) relapsed in the AS group and 16 patients (peritoneal recurrence, 4 patients; locoregional recurrence, 5 patients; distant recurrence, 8 patients; tumor marker recurrence, 1 patient) relapsed in the CAPOX group; some patients had multiple recurrence sites. 2 patients (1 patient for GAC; 1 patient for other diseases) died in the AS group and 11 patients (9 patients for GAC; 2 patients for other diseases) died in the CAPOX group. The median relative dose intensity of nab-paclitaxel was 90.32%, of S-1 was 80.77%, of oxaliplatin was 77.44% and of capecitabine was 78.55%. The incidence of adverse events (AEs) of any grade and grade 3/4 were 79.49% and 39.74% in the AS group, 72.61% and 22.93% in the CAPOX group. In the AS and CAPOX groups, neutropenia (31.63% vs 20.13%), leukopenia (29.71% vs 17.25%), anemia (27.80% vs 23.00%) and thrombocytopenia (4.15% vs 17.25%) were the most common AEs. Conclusions: Compared with CAPOX regimen, AS regimen has better survival rates and acceptable tolerability. AS provided new potential adjuvant regimen for stage III gastric cancer after D2 resection. Clinical trial information: NCT04135781.