Trastuzumab has substantial antitumor activity in metastatic gastric cancer. One such mechanism by which it exerts its antitumor activity is antibody-dependent cell-mediated cytotoxicity, which has been reported to be influenced by Fc gamma RIIA and IIIA polymorphisms. This study is the first to assess their impact on trastuzumab efficacy in patients with metastatic gastric cancer. We retrospectively examined 42 Her-2-positive patients receiving fluorouracil and platinum-based chemotherapy and trastuzumab, and 68 Her-2-negative patients receiving fluorouracil and platinum-based chemotherapy only as the first-line treatment. Fc gamma RIIA and IIIA polymorphisms were assessed, and their associations with efficacy in both settings were analyzed. In patients treated with trastuzumab, the Fc gamma RIIA H/H genotype was associated with significantly superior progression-free survival (PFS) (hazard ratio [HR] [95% CI]: 0.36 [0.16-0.82], adjusted HR [95% CI]: 0.18 [0.07-0.48], P=0.001). When combining Fc gamma RIIA and IIIA polymorphisms, the Fc gamma RIIA H/H or Fc gamma RIIIA V/V genotype was associated with a significantly improved disease control rate (P=0.04) and PFS (HR [95% CI]: 0.29 [0.13-0.67], adjusted HR [95% CI]: 0.17 [0.07-0.45], P < 0.001). As expected, no association of Fc gamma RIIA and IIIA polymorphisms with efficacy was found in patients receiving chemotherapy only. We concluded that Fc gamma RIIA and IIIA polymorphisms might predict disease control rate and PFS in metastatic gastric cancer patients receiving trastuzumab treatment.