Background: S-1 plus cisplatin (SP) is one of the standard first-line chemotherapies for AGC in the East Asia. Oxaliplatin is generally less toxic and more convenient than cisplatin. This study compared the safety and efficacy of S-1 plus oxaliplatin (SOX) with those of SP. Methods: This SOPP study was a multi-center, randomized, open-label, phase III study to evaluate whether SOX was non-inferior / superior to SP in terms of progression-free survival (PFS) according to RECIST v1.1. Patients (pts) with metastatic or recurrent gastric or gastroesophageal junction adenocarcinoma and no prior chemotherapy were randomized 1:1 to receive either SOX (S-1 80 mg/m²/day on D1-14, oxaliplatin 130 mg/m² on D1, every 3 weeks) or SP (S-1 80 mg/m²/day on D1-14, cisplatin 60mg/m² on D1, every 3 weeks) until disease progression or unacceptable toxicities. Results: Between October 2012 and October 2014, a total of 338 pts were randomized from 10 sites in Korea. The median age was 56 years (range, 26-80). 98% of pts had ECOG performance status 0-1. 51% of pts had measurable lesions. With a median follow-up of 15.6 months (range, 0.1-33.3) in surviving pts, SOX was significantly non-inferior but not superior to SP in PFS (median 5.6 months vs. 5.7 months; HR 0.85, 95% CI 0.67-1.07, p = 0.169). In pts with measurable disease, overall response rates (ORR) were similar between SOX and SP (58% vs. 60%, p = 0.7). Overall survival (OS) of both groups was not different, either (median 12.9 vs. 11.4 months; HR 0.86, 95% CI 0.66-1.11, p = 0.242). Treatment was generally well tolerated in both arms. While grade 3/4 neutropenia and febrile neutropenia were more common in SP, grade 3/4 peripheral neuropathy and thrombocytopenia were more common in SOX. Conclusions: SOX was non-inferior to SP in terms of PFS, ORR, and OS. The two regimens were well tolerated with different toxicity profiles. SOX regimen can be also recommended as a first-line treatment of AGC. Clinical trial information: NCT01671449