To investigate the prevalence of pS2 expression in gastric cancer with respect to tumor histopathology, intestinal metaplasia and Helicobacter pylori (H. pylori) infection, pathologic specimens of 91 patients with gastric cancer were immunostained for pS2. Such immunoreactivity was correlated with the status of H. pylori infection, tumor staging, histology, subtyping, and associated intestinal metaplasia. Positive pS2 staining was seen throughout all non‐neoplastic epithelia, and in all 9 patients with the complete type of intestinal metaplasia. In contrast, 21 of 45 incomplete type of intestinal metaplasia had negative pS2 staining (P<0.001), and 54 out of 91 tumors (59.3%) showed loss of pS2 expression in the cancer tissues proper. There was no correlation of pS2 expression with age, gender, depth of invasion, duodenal involvement, lymph node metastasis, venous invasion or H. pylori infection. Negative pS2 staining was significantly higher in the intestinal (74.5%) and Borrmann type I, II, III (64.2%) tumors than the diffuse (43.2%, P<0.005) and Borrmann type IV (20%, P<0.05) tumors. Our results indicate that loss of pS2 expression may occur as an early event in the malignant transformation process of intestinal‐type tumors.