Background: Two functional polymorphisms of the microsomal epoxide hydrolase (mEH) gene (EPHX1), Tyr113His (rs1051740) and His139Arg (rs2234922), have variably been found to influence susceptibility to various cancer forms. We tested whether genetically lowered mEH activity affects risk of developing cancer in the general population. Methods: We genotyped 47,089 individuals from the Danish general population for the Tyr113His and His139Arg polymorphisms in the EPHX1 gene and divided them into groups with predicted fast, intermediate, and slow mEH activity. Using Cox proportional hazards models, we calculated HRs for 26 individual cancer diagnoses and for groups of any cancer, tobacco-related cancers, estrogen-related female cancers, and other cancers. Results: Of the 47,089 individuals, 7,590 experienced a cancer event, and of these, 1,466 were tobacco-related. After multifactorial adjustment, the HRs (95% CI) for tobacco-related cancer were 1.1 (0.8-1.5) and 1.5 (1.1-2.0) in individuals with intermediate and slow mEH activity versus individuals with the fast phenotype (P trend = 0.003). The corresponding HRs among ever-smokers were 1.1 (0.8-1.5) and 1.5 (1.1-2.0; P trend = 0.003), whereas HRs among never-smokers did not differ from 1.0. Conclusions: Our results indicate that genetically lowered mEH activity is associated with increased risk of developing tobacco-related cancer among smokers in the general population; however, additional studies are needed to confirm our findings. Impact: To our knowledge, this is the largest study to investigate the association of mEH phenotype and genotype with tobacco-related cancers combined in the general population.