Inflammatory responses to environmental exposures, such as tobacco smoke, may play a role in lung carcinogenesis. To test this hypothesis, we studied genetic polymorphisms in the inflammation pathway in relation to lung cancer risk. We evaluated a panel of 59 single nucleotide polymorphisms (SNP) in 37 inflammation-related genes among non-Hispanic Caucasian lung cancer cases (N=1,553) and controls (N=1,730) from Houston, Texas. Logistic regression was used to assess associations with lung cancer under a dominant genetic model adjusted for sex, age, and smoking. Haplotypes were estimated with the expectation-maximization algorithm. False-positive report probabilities (FPRP) were calculated for significant associations. Interleukin 1 beta (IL1B) C3954T was associated with lung cancer [odds ratio (OR), 1.27; 95% confidence interval (95% CI), 1.10-1.47; FPRP 0.148]. Two IL1A SNPs (C-889T and Ala(114)Ser) were also related to lung cancer (OR, 1.18-1.22), although FPRPs were higher. One IL1A-IL1B haplotype, containing only the IL1B 3954T allele, was associated with elevated lung cancer risk (OR, 1.80; 95% CI, 1.24-2.61). These associations were stronger in heavy smokers, particularly for IL1B C3954T (OR, 1.59; 95% CI, 1.28-1.97; FPRP 0.004). Lung cancer risk was unrelated to polymorphisms in IL1 receptor or antagonist genes. Associations with lung cancer were also seen for SNPs in granulocyte macrophage colony stimulating factor and peroxisome proliferator-activated factor-delta, but FPRPs were high. IL1A and IL1B polymorphisms are associated with increased lung cancer risk, especially among heavy smokers. IL1A and IL1B are critical signals in initiating inflammation. Our results suggest that a dysregulated inflammatory response to tobacco-induced lung damage promotes carcinogenesis.