Epidemiological studies suggest that bladder cancer may be caused by carcinogens in tobacco and certain occupational exposures. Molecular studies have shown that chromosome 9 alterations and TP53 mutations are the most frequent events in bladder cancer. To date, the relationships between epidemiological risk factors and genetic alterations have not been fully explored in bladder cancer. The purpose of this study was to explore the association between smoking and chromosome 9 aberrations in bladder cancer cases. Seventy-three patients with bladder cancer at Memorial Sloan-Kettering Cancer Center were evaluated for smoking history, occupational history, and chromosome 9 alterations. The epidemiological data were abstracted from medical charts. Patients' tumor tissues were analyzed using RFLP and microsatellite polymorphism assays for detection of chromosome 9 alterations. Elevated odds ratios (ORs) were found for chromosome 9 alterations in smokers compared to those in nonsmokers (OR = 4.2; 95% confidence interval, 1.02-17.0) after controlling for age, sex, race, occupational history, and stage of disease. The ORs were 3.6 for those smoking < or = 20 cigarettes per day and 5.8 for those smoking > 20 cigarettes per day. No association was found between occupational history and chromosome 9 alterations. This study supplies evidence suggestive of the link between smoking and chromosome 9 alterations in the etiology of bladder cancer and indicates that potential tumor suppressor genes on chromosome 9 may be involved in smoking-related bladder carcinogenesis.