Epstein-Barr virus (EBV) infection was studied in a total of 412 patients with poorly differentiated gastric adenocarcinoma by in situ hybridization for EBV-encoded small RNA. EBV-specific RNA was detected in tumor cell nuclei of 83 (20.1%) of 412 gastric carcinomas, of which 60 were histologically subclassified as gastric carcinoma with lymphoid stroma (GCLS). All EBV-positive gastric carcinomas as well as 90 randomly selected EBV-negative gastric carcinomas were further studied for p53 protein expression by immunohistochemistry. The overexpression of p53 protein was demonstrated in only 7 (8.4%) of 83 EBV-positive gastric carcinomas. This was in marked contrast to the frequency of 34.4% in EBV-negative gastric carcinomas. In addition, a few p53-positive nuclei were characteristically scattered in the tumors of many EBV-positive GCLS, but this was not regarded as p53 overexpression arising from mutation of the gene. Our findings suggested that EBV-associated gastric carcinomas may arise through a different mechanism from other types of gastric carcinomas without EBV infection.