This study was performed to evaluate p53 overexpression as a predictor of the response to chemotherapy of patients with gastric cancer. The subjects comprised 20 patients with Stage IV gastric cancer and three with locally recurrent lesions, all of whom were treated with 5-fluorouracil (5-FU) plus cisplatin (CDDP) for 4 weeks. Of the total 23 patients there were 10 responders; 2 showing complete response (CR) and 8, partial response (PR). Specimens obtained by endoscopic biopsy were immunohistochemically stained using anti-p53 protein and bcl-2 protein antibody. Of the 10 responders, 7 demonstrated negative p53 staining, and of the 13 nonresponders, 11 demonstrated positive p53 staining (P = 0.013). Tissue from 3 of the responders and 7 of the nonresponders that stained for bcl-2 were positive prior to chemotherapy; however, there was no association between bcl-2 staining and chemotherapeutic effect. In conclusion, immunohistochemical identification of p53 in pretreatment tissue may represent a useful predictor for chemotherapeutic outcome in patients with gastric cancer.