Background: Despite a large number of randomized trials, there is no global consensus as to the standard regimen for front-line chemotherapy of recurrent/metastatic gastric cancer. We conducted a randomized phase II study to compare 4 doublet regimens, S-1 and cisplatin (SP); FOLFOX; docetaxel and 5-FU (DF); and paclitaxel and 5-FU (TF), for their therapeutic efficacy and safety as a first line treatment. Methods: Patients with no prior chemotherapy for recurrent/metastatic gastric adenocarcinoma were enrolled and randomized evenly to each regimen. The primary endpoint was progression free survival (PFS), and secondary endpoints were overall survival (OS), response rate (RR), and safety profile. Analysis was performed by intention to treat. Results: A total of 177 patients were enrolled from MAR 2010 to MAY 2015. Four treatment arms were well-balanced: median age 57, male 69.5%, and ECOG performance 0/1/2 = 61/37/2%. At data cutoff (DEC 31, 2015), median PFS were 8.6 (3.5-13.7) months for SP, 5.8 (2.9-8.7) months for FOLFOX, 6.8 (2.4-11.2) months for DF, and 4.6 months for TF (3.6-5.6) (p = 0.054). Median OS were 14.7 months for SP, 11.3 months for FOLFOX, 11.7 months for DF, and 10.7 months for TF (p = 0.208), and RR were 17.8% for SP, 21% for FOLFOX, 16% for DF, and 33% for TF). In terms of platinum- and taxane-based regimens, the PFS and OS did not differ significantly (PFS: 7.2 vs. 5.7 months; p = 0.207, OS: 13.3 vs. 11.7 months; p = 0.701). Toxicity was generally well tolerated, with grade 3-4 neutropenia observed in 33.3% of SP, 9.3% of TF, 55.6% of DF, and 45.5% of FOLFOX arm, while febrile neutropenia was observed in only 1 patient in SP arm and 2 patients in DF arm. There was no treatment-related mortality. Conclusions: Although none of the 4 regimens revealed significant superiority over others in the treatment of recurrent/metastatic gastric cancer, SP regimen showed a tendency of increased PFS and OS compared with other regimens. Clinical trial information: NCT01283204