Background: Recently the efficacy of trastuzumab (T-mab) for HER2-positive gastric cancer has been reported. We have developed a triplet-drug combination regimen consisting of docetaxel, CDDP, and S-1 (DCS) and reported that the regimen provides very high response rates (BJC 2007; CCP 2009 and 2013). To increase the efficacy of DCS in patients (pts) with HER2-positive unresectable gastric cancer, we carried out a feasibility study for the DCS-T-mab (DCS-T) regimen. Methods: Eligibility criteria included the following: age between 20 and 80 years; unresectable HER2-positive metastatic gastric cancer; normal cardiac function. Pts received oral S-1 (40 mg/m² b.i.d.) on days 1-14, intravenous cisplatin (60 mg/m²), docetaxel (50 mg/m²) and T-mab (8 mg/kg in the first cycle and 6 mg/kg in the second cycle and thereafter) on day 8 every 3 weeks. Results: This study included 16 pts: median age, 60 years (34 – 76 years), 11 males and 5 females. PS 0/1/2, 10/4/2; differentiated/undifferentiated-type histology, 11/5; U/M/L, 7/8/1; HER2 3+, 13; HER2 2+/FISH+, 3; T3/T4a/T4b, 11/4/1; N0/N1/N2/N3, 2/0/4/10; and distant lymph nodes/liver/peritoneum/lungs/bone/ovaries, 11/7/4/2/1/1. The completion rate until the third cycle was 100%. According to the RECIST criteria, the objective response rate was 93.3%, and the median cycle to response was 1 (1–3 cycles). Adverse events of grade 3 or greater severity were: leukopenia/neutropenia, 68.8/81.3%; FN, 12.5%; anorexia, 25%; and diarrhea, 25%. All of these side effects were well controlled. Non-curative factors disappeared in 7 of 16 cases and R0 resection was carried out in 6 cases (37.5%) including 2 pts with liver metastases. A pathological response was found in 83 % of 6 resected cases. At a median follow-up of 9.8 months (2.3 – 23 months), median PFS was 12.8 months and median OS was not yet reached. Conclusions: T-mab in combination with DCS is a feasible regimen in pts with unresectable HER2-positive gastric cancer. The observed response rate is very promising and warrants further investigation. Clinical trial information: UMIN000005603.