Overexpression of p53 is considered to be predictive of mutations of the p53 gene. Exposure-specific mutations of the p53 gene have been described for cancers at different sites. An association between p53 mutation/overexpression and smoking has been described in early stage bladder cancer, but results were conflicting. We have conducted a study on 131 bladder cancer cases, considering p53 expression and smoking habits in an area where the use of air-cured tobacco, rich in carcinogenic arylamines, is common. The study suggests that the use of air-cured tobacco induces p53 overexpression (possibly via mutation) in early stage-low grade bladder cancer, more frequently than flue-cured tobacco (odds ratios = 3.4, 95% confidence intervals 0.9-13 in stage 1; odds ratios = 24, 95% confidence intervals 1.1-519 in stage 1, grade 1). However, all the excess associated with air-cured tobacco was concentrated in recurrences. When available, the biopsies of recurrent cases with early-stage disease were re-examined and all showed p53 expression at first diagnosis (with 10-50% of cells positive) (n = 5). It is hypothesized that exposure to tobacco-related chemicals increases the risk of recurrences via p53 overexpression/mutation. Expression of the bcl-2 gene was detected in only 2 out of 13 p53-positive smokers.