Background: HER2 is a valid therapeutic target in advanced gastric cancer, however the prognostic significance of HER2 in this disease remains unknown. This analysis was performed to evaluate the prognostic significance of HER2 gene amplification or protein overexpression (HER2+) in advanced gastric cancer. Methods: Paraffin-embedded tumor samples of gastric cancer pts from six prospective first-line therapeutic trials of chemotherapy without trastuzumab performed in the U.S. and Europe were examined for HER2 by immunohistochemistry (IHC, 4B5) and in situ hybridization ISH (FISH or HER2 Dual ISH). HER2 positive disease (HER2+) was defined as IHC 3+ or ISH+ (ISH >2.0 HER2:CEP17 FISH or HER2 Dual ISH). The impact of HER2 status was correlated with pt outcome using univariate and multivariate analysis. Results: 338 pts were evaluated: age 64 (28-88), M/F 233/105, GEJ/gastric 132/156, PS 0-1 224, Intestinal/Diffuse 125/140. 20.4% of all pts are HER2+. There were significant differences in HER2+ rates according to histological type (intestinal/mixed, 29%; diffuse, 8%; p<0.001), sex (M, 25%; F, 11%; p=0.012), and ECOG PS (0-1, 22%; 2-3, 10%; p<0.001). Similar rates of HER2+ tumors were found in biopsies vs. resections (22% vs. 19%) and in primary tumors vs. metastases (21% vs. 16%). Median overall survival was significantly longer in HER2+ pts (13.4 vs. 11.6 mos, HR 0.74; p=0.048) on univariate analysis. This prognostic value disappeared in multivariate analysis (p=0.3). In addition, HER2+ disease was not prognostic in subgroup analysis based on tumor histology. Factors associated with favorable survival in the multivariate analysis were intestinal type, female sex, recurrent disease, and ECOG PS 0-1. Conclusions: Approximately 20% of Western patients with advanced gastric cancer are HER2+. Although on univariate analysis, HER2+ was associated with improved overall survival, this was not independent of other known prognostic variables. Unlike breast cancer where HER2+ disease carries an adverse prognostic value, HER2+ disease is not an independent prognostic factor for pt outcome in advanced gastric cancer.