Aims and background: The HER2 gene encodes a 185-kd transmembrane glycoprotein receptor (p185HER2) that has partial homology with the epidermal growth factor receptor and shares intrinsic tyrosine kinase activity. The phosphatase and tensin homolog mutated on chromosome ten (PTEN) gene product is a protein tyrosine phosphatase that participates in modulating the phosphoinositide 3-kinase pathway which has antagonizing activity to protein tyrosine kinase. The authors investigated the correlation between clinicopathologic variables including survival and the overexpression of the p185HER2 with loss of PTEN expression in gastric adenocarcinoma patients. Methods: The protein expression of p185HER2 and PTEN was examined by immunohistochemical stain in paraffin-embedded tissues of 94 (M:F, 52:42) gastric adenocarcinoma patients by using monoclonal antibody, and the results were related to clinicopathological variables and survival. Results: p185HER2 overexpression correlated positively with lymph node metastasis, distant metastasis, AJCC classification, higher relapse rate. Patients with overexpression of p185HER2 were found to have significantly lower disease-free survival (P = 0.003) and overall survival (P = 0.0004). Loss of PTEN expression correlated positively with depth of invasion (T stage) and was more frequent in the advanced stage. The patient group with p185HER2 overexpression and loss of PTEN expression showed significantly shorter disease-free and overall survival (P = 0.03, P = 0.01) than the other groups. Conclusions: Our observations suggest potential prognostic significance of p185HER2 overexpression with PTEN loss in gastric adenocarcinoma patients. This opens up the possibility of considering p185HER2 and PTEN as a therapeutic target in gastric cancer.