The role of low penetrance genes and environmental factors in the etiology of prostate cancer (PCa) is unclear. Most procarcinogens require metabolic activation by CYP4501A1, whereas microsomal epoxide hydrolase (mEH) is involved in the detoxification. In our case-control study, we assessed whether CYP1A1 and mEH susceptibility genotypes, tobacco use, and age factors contribute to PCa risk. One hundred thirty patients with PCa and 140 control subjects were analyzed by polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) method from genomic DNA samples. Binary logistic regression model was used for assessing differences in genotype prevalence and their association between patient and the control group. T/C polymorphism of CYP1A1 gene revealed significant association with the tobacco users (p < 0.005) for PCa risk. Our results demonstrated significant association with exon 3 variant genotypes of the mEH alone or in combination with tobacco users (p < 0.005), whereas in exon 4 genotypes, no association was observed. Haplotype analysis projected significant associations with very slow haplotypes of mEH gene (OR = 2.48, 95% CI = 1.41-4.38, p = 0.002). In conclusion, our study demonstrated that exon 3 of mEH and CYP1A1 T/C gene polymorphism are predisposing risk factors for susceptibility of sporadic PCa in northern India. It also suggests that a combination of smoking plays a significant role in modified PCa risk on the study population, which means that smokers carrying susceptible genotypes may be subjected to higher risk than those carrying nonsusceptible genotypes.