Matrix metalloproteinases (MMPs) play an important role in several steps of cancer development. A single nucleotide polymorphism (-1306C-->T) in the MMP2 promoter sequence disrupts an Sp1 site and thus results in strikingly lower promoter activity. We examined the relationship between this polymorphism and risk for lung cancer in 781 cases and 852 age- and sex-matched controls in a Chinese population. We found that the allele frequency of MMP2-1306C was significantly higher among cases than among controls (0.91 versus 0.83). Subjects with the CC genotype had an overall 2-fold increased risk for developing lung cancer [adjusted odds ratio (OR) 2.18; 95% confidence interval (CI), 1.70-2.79] compared with those with the CT or TT genotype. The elevated risk was observed evenly among different subtypes of this cancer. Stratified analysis indicated an additive interaction between the CC genotype and smoking on the elevated risk. The ORs of lung cancer for the CC genotype, smoking, and both factors combined were 2.38 (95% CI 1.64-3.45), 4.26 (95% CI 2.57-8.44), and 7.64 (95% CI 4.74-12.33), respectively. Furthermore, when the data were stratified by the pack-years smoked, this joint effect was more evident and stronger in heavy smokers (OR 10.25, 95% CI 5.80-18.09) than in light smokers (OR 5.55, 95% CI 3.34-9.22). These results demonstrate a significant association between the MMP2 -1306C/T polymorphism and risk of developing lung cancer solely or in a manner of interaction with carcinogen exposure.