DNA mismatch repair (MMR) plays an important role in maintaining genome stability. Defects in MMR genes have been involved in several types of sporadic and hereditary cancers. hMLH1 is considered one of central members of the MMR pathway. We conducted a hospital-based case-control study to investigate associations of common variations in the hMLH1 gene and risk of lung cancer. A total of 500 cases and 517 controls were genotyped for seven SNPs in hMLH1. Overall, the rs1799977 I219V polymorphism was marginally associated with the risk of lung cancer (P=0.055). This association was much stronger in younger patients (P=0.01; odds ratio, 5.28; 95% CI 1.45-19.21) and lung squamous cell carcinoma (P=0.006; odds ratio, 3.65; 95% CI 1.44-9.24). These findings indicate that the hMLH1 rs1799977 polymorphism may contribute to the etiology of early-onset lung cancer as well as some specific subtype of lung cancer. Larger association studies are warranted to validate our findings and mechanistic studies are needed to elucidate the underlying molecular mechanisms of the association.