The human microsomal epoxide hydrolase (EH) gene contains polymorphic alleles which are associated with altered EH activity and may be linked to increased risk for tobacco-related cancers. The objective was to examine the role of EH polymorphisms in orolaryngeal cancer risk. The prevalence of the EH codons 113 and 139 polymorphisms were examined in 81 African American and 142 Caucasian incident orolaryngeal cancer patients and 335 controls frequency-matched on age, sex, and race. In Caucasians, a significant risk increase was observed for subjects with the EH(113Tyr) variant (OR=2.1, 95% CI=1.1-4.0) and predicted high-activity EH genotypes in heavy-smokers (>or=35 pack-years; OR=3.4, 95% CI=1.2-9.6). A significant association between predicted high EH activity genotypes and orolaryngeal cancer risk was observed in Caucasian subjects with the GSTM1 null (OR=3.5, 95% CI=1.3-9.3) but not GSTM [+] (OR=0.9, 95%CI=0.4-2.1) genotype. These results suggest that EH polymorphisms play an important role in risk for orolaryngeal cancer in Caucasians.