Prostaglandin synthase 2 (PTGS2) mediated production of prostaglandins is an important step in the inflammatory response. In a population-based case-cohort study, we investigated the relationship between lung cancer and a polymorphism in PTGS2 at site 8473. Among 54,220 cohort members, 265 lung cancer cases and a comparison group of 272 individuals were identified. We found no overall significant association between the PTGS2 polymorphism and lung cancer risk, though the results indicated a lower risk in subjects carrying one copy (RR 0.87; 95% CI 0.61-1.25) or two copies (RR 0.58; 95% CI 0.30-1.12) of the variant allele compared with subjects carrying two copies of the wildtype allele. This tendency seemed to be strongest among the youngest subjects (50-55 years) with a RR on 0.48 (0.19-1.22) in carriers of one variant allele and 0.21 (0.04-1.07) in carriers of two variant alleles, and a significant trend (P=0.04). These results indicate that PTGS2 could be implicated in the development of lung cancer.