O6-methylguanine, a methylated damage lesion in DNA, correlates with spontaneous G:C --> A:T transition mutations and leads to activation of oncogene K-ras or dysfunction of the tumor suppressor gene p53. O6-methylguanine-DNA methyltransferase (MGMT) is critical for repairing damage to the O6-position of guanine. Therefore, we tested our hypothesis that genetic variants of MGMT are associated with increased lung cancer risk in a Caucasian population of 1,121 lung cancer patients and 1,163 matched cancer-free controls. We genotyped four potentially functional single nucleotide polymorphisms (SNPs) of MGMT: exon 3 codon 84C --> T (L84F), exon 5 codon 143A --> G (I143V), and two promoter SNPs 135G --> T and 485C --> A. The allele frequency distributions of the SNPs of codon 84C --> T and the promoter 135G --> T in the cases were borderline different from that in the controls. After defining the minor allele (T for codon 84C --> T and G for codon 143A --> G) as the variant allele, we categorized the MGMT genotypes as either 0 variants (84CC-143AA) or 1-4 variants. Compared with 0 variants, those with 1-4 variants showed a statistically significantly increased risk of lung cancer (P = 0.040). Further stratification analysis showed that this increased risk was more pronounced in women, current smokers, and non-small cell lung cancer. We did not find any association between the MGMT promoter SNPs and lung cancer risk. Our findings suggest that non-synonymous SNPs in MGMT are associated with modestly increased risk of lung cancer in Caucasians and need to be further investigated.