Extracellular matrix-degrading matrix metalloproteinase-1 (MMP-1) is an interstitial collagenase that degrades the interstitial types I, II, and III collagens, and overexpression of MMP-1 is associated with cancer development and cellular invasion. The 2G allele of the MMP-1 -1607 1G/2G polymorphism is associated with enhanced transcriptional activity. We investigated the association between the MMP-1 1G/2G polymorphism and lung cancer risk in 1,752 Caucasian lung cancer patients and 1,363 healthy controls. There were no overall associations between the MMP-1 genotypes and risk of lung cancer, with the adjusted odds ratios of 1.15 [95% confidence interval (CI), 0.94-1.40] for the 1G/2G genotype and 1.14 (95% CI, 0.90-1.45) for the 2G/2G genotype, when versus the 1G/1G genotype. Stratified analyses suggested higher lung cancer risk for the 2G allele in never-smokers and males, with the adjusted odds ratios of 1.67 (95% CI, 1.02-2.76; 1G/2G) and 1.50 (95% CI, 0.86-2.62; 2G/2G) in never-smokers; and 1.30 (95% CI, 1.00-1.75; 1G/2G) and 1.23 (95% CI, 0.88-1.73; 2G/2G) in males, respectively. In conclusion, genotypes containing the 2G allele of the MMP-1 polymorphism are associated with higher risk of lung cancer in never-smokers and in males.