BACKGROUND: The arylamine N-acetyltransferases play a major role in the metabolic activation of carcinogenic amines that are present in cigarette smoke and a variety of other exogenous sources. The objective of this study was to determine the association of rapid or slow arylamine N-acetyltransferase (NAT) genotypes with smoking history and the risk for developing both bladder and prostate cancer. PATIENTS AND METHODS: The subjects analyzed were a case group of 17 double-cancer patients and 34 age-matched controls who had benign prostatic hypertrophy, but were asymptomatic for prostate or bladder cancers. Genotyping of NAT1 and NAT2 alleles was done by restriction fragment length polymorphism and/or sequencing of NAT genes amplified from genomic DNAs by the polymerase chain reaction (PCR). RESULTS: No significant correlation was found between NAT1 genotypes, double cancer, and smoking history. While NAT2-smoking interaction gave an odds ratio of only 1.70 (p = 0.117), a disproportionate number of cancer cases were genotypically rapid: 12 of 17 cancer cases vs. 13 of 34 controls (odds ratio 3.88; p = 0.040). CONCLUSION: Rapid NAT2 genotype correlated significantly with the development of double prostate-bladder cancer.