The mutation patterns of the p53 tumor suppressor gene have been shown to reflect the specific carcinogen(s) involved, or the epidemiological background in some cancers. To elucidate the impact of cigarette smoking or bilharzial infection on the p53 gene mutation pattern, 61 cases of urothelial cancer from Japan and 7 cases of bladder cancer with schistosomiasis from Egypt were examined for mutations of the p53 gene. In total, p53 gene mutations were detected in 20 Japanese cases (33%) and 6 Egyptian cases (86%). Although the incidence of p53 gene mutation was not significantly influenced by habitual smoking, a different mutation pattern was observed as follows: 4 of 10 mutations in smokers in Japan were A:T to G:C transitions, whereas such mutations were not detected in any of 10 mutations in nonsmokers, or in any of 6 mutations associated with schistosomiasis. Although no specific mutation pattern was detected for the squamous cell carcinomas with schistosomiasis, all 8 base substitutions observed in tumors with squamous cell carcinomas occurred at G:C sites, whereas base substitutions at A:T sites were observed in 33% (6 of 18) of mutations in transitional cell carcinomas. Our results suggest that cigarette smoking may have a significant impact on the mutations of the p53 gene in urothelial cancers. Furthermore, the distinct spectrum of the p53 gene mutation found in tumors with squamous cell carcinomas may reflect their unique etiological backgrounds.