Few studies have assessed mutagen sensitivity and lung cancer (LC) risk associations in the context of multiple epidemiological risk factors. We evaluated mutagen sensitivity as a susceptibility marker and explored the interplay of the genetic marker and multiple epidemiologic risk factors in modulating LC risk. This largest case-control study included 977 newly diagnosed LC patients and 977 controls, matched by age, gender, ethnicity and smoking status. Cases exhibited significantly higher mutagen sensitivity than controls in bleomycin (0.76 vs. 0.62 breaks/cell, p < 0.001) and benzo[a]pyrene diol epoxide (BPDE) assays (0.70 vs. 0.61 breaks/cell, p < 0.001). Mutagen sensitivity also exhibited dose-response relationship with LC risk in quartile analysis (p for trend <0.001). In smokers, history of emphysema, absence of hay fever history, LC in first-degree relatives, belomycin sensitivity, and high pack-year were identified to be the top 5 significant risk factors in a stepwise logistic regression model (odds ratios (ORs) of 2.69, 1.91, 1.84, 1.73 and 1.67, respectively). Analyses of joint effects of risk factors showed that compared to the reference group, subjects with no exposure to any of the aforementioned risk factors, the ORs for exposure to 1, 2, 3, 4, 5 or more of the risk factors were 1.56, 2.39, 3.75, 6.74 and 17.39, respectively (p for trend <0.001). This study strongly supports mutagen sensitivity as a predisposition factor for LC and demonstrates the importance of assessing multiple risk factors to comprehensively assess LC risk. This new integrative approach should facilitate identification of high-risk subgroups and has important implications in LC prevention.