Background: Cisplatin and S-1 (CS) regimen is one of the standard chemotherapy as first-line for advanced gastric cancer. Docetaxel is a well-known agent with high anti-tumor effect for peritoneal metastasis from gastric cancer. A previous phase III study showed docetaxel plus S-1 (DS) regimen was recommended especially for advanced gastric cancer without measurable lesions. However, there was no study comparing the efficacy and safety of these two regimens. Methods: Eligibility criteria included HER2-negative unresectable or recurrent gastric adenocarcinoma, no measurable lesion according to RECIST v1.1, no massive peritoneal metastasis, no prior chemotherapy or radiotherapy, age ≤75, PS 0-2, adequate oral intake, and preserved organ functions. Patients were randomized to receive CS (cisplatin 60 mg/m² on day 8, S-1 40–60 mg twice a day for 3 weeks, every 5 weeks) or DS (docetaxel 40 mg/m² on day 1, S-1 40–60 mg twice a day for 2 weeks, every 3 weeks). Primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS) and adverse events. Results: Sixty-one patients were randomly allocated the CS group (n = 31) or the DS group (n = 30) between Aug 2011 and Sep 2015. All were unresectable primary cases, and baseline characteristics were well balanced between the two groups. One patient was ineligible due to HER2-positive. There was no treatment-related death. The main grade 3 or worse adverse events were neutropenia (27% in CS vs. 40% in DS), anemia (10% in CS vs. 10% in DS), fatigue (13% in CS vs. 7% in DS), anorexia (10% in CS vs. 3% in DS), and diarrhea (10% in CS vs. 3% in DS). The median OS time were 15.8 months in CS and 20.0 months in DS, respectively (log-rank P = 0.113). Hazard ratio for OS was 0.617 (95%CI, 0.337 – 1.128). The median PFS time were 9.6 months in CS and 11.2 months in DS, respectively (log-rank P = 0.196). Hazard ratio for PFS was 0.698 (95%CI, 0.404 – 1.208). Conclusions: DS showed less toxic and more active profiles than CS for treatment of advanced gastric cancer without measurable lesions. The clinical benefit of DS regimen should be demonstrated in a phase III study. Clinical trial information: UMIN000006179.