Purpose: WW domain-containing oxidoreductase (WWOX) is a tumor suppressor gene that maps to the common fragile site FRA16D on chromosome 16q23.3-24.1. To investigate the role of the WWOX gene in the development of gastric carcinoma, we examined a large series of primary adenocarcinomas and nine gastric cancer cell lines for the expression of Wwox. Experimental Design: Loss of heterozygosity, reverse-transcription-PCR, and immunohistochemistry were used to assess the role of WWOX in stomach cancer. A total of 81 primary gastric adenocarcinoma were analyzed. Results: Loss of heterozygosity was observed in 31% of the cases and loss of Wwox protein expression was found in 65% of gastric adenocarcinoma primary specimens and 33% of gastric cancer cell lines. In addition, we found a high correlation between Wwox and Fhit protein expression. Conclusions: Our results indicate that alterations of the WWOX gene may be involved quite frequently in gastric tumorigenesis. Our data could be used in future studies to develop diagnostic and targeted therapy of stomach cancer.