Distribution and gene-environment interaction of EPHX1 polymorphism was evaluated in 175 lung cancer patients and 322 controls from north India. Two novel non-synonymous, Lys117Arg and Leu263Phe, and twelve single nucleotide polymorphisms were identified in the present study. Binary logistic regression analysis showed association of polymorphism Tyr113His with increased risk of lung cancer (OR = 2.2, 95% CI = 1.2-4.0, p < .05). Gene-environment interaction revealed that patients with His113His and smoking habit had significantly greater risk of lung cancer (OR = 4.52, 95% CI = 0.93-43.05, p < .05). Present study provided evidence that EPHX1 polymorphism is associated with lung cancer susceptibility in Indian population.