We have hypothesized that consumption of fruit and vegetables may be associated with reduced risk of bladder cancer and that this may interact with cigarette smoking and metabolic genetic polymorphisms. A population-based case-control study was performed in the Belgian province of Limburg among 200 cases and 385 controls. Logistic regression was performed to calculate odds ratios (ORs) for bladder cancer occurrence with corresponding 95% confidence intervals (95% CI). Effect modification by smoking was investigated. We also evaluated interaction between fruit intake and GSTM1, GSTT1, NAT2 and SULT1A1 amongst "ever-smokers." Total vegetable intake was not significantly associated with the risk of bladder cancer (OR 1.15, 95% CI: 0.70-1.88 for the highest compared to the lowest tertile). However, total fruit intake was negatively associated with bladder cancer risk (OR 0.61, 95% CI 0.37-0.99 comparing the same tertiles). Among individuals with low daily fruit consumption, ever smokers had a highly increased risk of bladder cancer risk (OR: 4.23, 95% CI: 1.91-9.40). By increasing the daily fruit consumption, the risk of "ever-smokers" for developing bladder cancer decreased, however it remained significant (OR: 2.15; 95CI%: 1.15-4.05). No interaction was identified between the different genotypes and fruit consumption. We conclude that fruit consumption may decrease the effect of smoking on developing bladder cancer. Antioxidants, found in fruit, may protect against the damage caused by free radicals found in cigarette smoke. Metabolic polymorphisms appear not to modify this relation. (c) 2005 Wiley-Liss, Inc.