The risk of squamous cell cancers of the oral cavity (OSCC) is strongly related to the use of tobacco and alcohol. N-Acetyl transferases 1 and 2 (NAT2) metabolize aryl- and heterocyclic amines that are present in tobacco smoke. NAT2 slow acetylator phenotype or genotype is related to reduced ability to detoxify these xenobiotics that are carcinogenic in tissues in which smoking-related cancers develop (e.g. bladder). We studied the association between the deduced NAT2 acetylator phenotypes and OSCC risk in a population-based study of 341 cases and 552 controls. In-person interviews provided information on tobacco use and alcohol consumption. Nucleotide substitutions at position 191, 341, 590, 803 and 857 were determined by a combination of oligonucleotide ligation assays and PCR/RFLP assays. There was no overall association between acetylator status with OSCC risk; the odds ratios for slow and intermediate acetylators, as compared with the rapid acetylators, were 1.2 (95% CI 0.7-2.2) and 1.1 (95% CI 0.6-2.0), respectively. The percent increase in risk of OSCC per pack-year cigarette smoking was similar among slow acetylators (3.0%, 95% CI 2.1-4.0) and the combined intermediate and rapid acetylators (3.5%, 95% CI 2.4-5.0). In contrast, the risk of OSCC per weekly alcoholic drink was stronger among the combined rapid and intermediate acetylators (3.3%, 95% CI 1.8-4.9) compared with slow acetylators (1.6%, 95% CI 0.6-2.7) (interaction P = 0.055). These data raise the possibility that NAT2 may be involved in the activation of one or more pro-carcinogens associated with alcohol consumption.