Microsomal epoxide hydrolase (mEH) is involved in the bioactivation and detoxification of polycyclic aromatic hydrocarbons derived from tobacco smoke and charred meat intake. Two coding region mEH variants located in exon 3 (Tyr113His) and exon 4 (His139Arg) have been described and may affect the enzyme's specific activity. We investigated these polymorphisms and tested interactions with smoking and charred meat intake in relation to risk of colorectal adenoma in two case-control studies nested in the Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS) cohorts. mEH exon 3 and exon 4 polymorphisms were not associated with overall risk of adenoma among 556 incident cases and 557 controls from the NHS or 376 prevalent cases and 725 controls from the HPFS. A statistically significant interaction was found between the exon 4 polymorphism and smoking for men (P = 0.03) and a borderline significant interaction was found between the exon 3 polymorphism and smoking for women (P = 0.06). Women having the exon 3 'rapid' Tyr/Tyr genotype were at increased risk when exposed to either > or =25 pack-years smoking [relative risk (RR) = 2.43, 95% confidence interval (CI) 1.47-4.01] or <25 pack-years of smoking (RR = 1.73, 95% CI 1.10-2.73) relative to non-smokers. Men with the exon 4 'slow' His/His genotype were at increased risk when exposed to > or =25 pack-years smoking (RR = 2.21, 95% CI 1.43, 3.41) or <25 pack-years smoking (RR = 1.71, 95% CI 1.13-2.59) relative to non-smokers. Charred meat intake was not associated with adenoma risk and there was no significant interaction with either mEH polymorphism. Our results indicate that individuals exposed to > or =25 pack-years smoking were at increased risk for colorectal adenoma and that risk is related to dose of tobacco carcinogens and mEH activity level, but the results were not consistent between men and women.