We conducted a population-based case-control study in Xuan Wei, China, where lung cancer rates are among the highest in China due to exposure to indoor coal combustion products, to evaluate the association between polymorphisms in immunoregulatory genes and lung cancer risk. A total of 122 incident primary lung cancer cases and 122 individually matched controls were enrolled in Xuan Wei, China. Fifty single-nucleotide polymorphisms (SNPs) in 23 immunoregulatory genes involved in inflammation were genotyped and analyzed by logistic regression to assess the risk of lung cancer. A global test of association for 42 SNPs, which excluded eight SNPs that were in very tight linkage disequilibrium with other SNPs, was statistically significant (P = 0.01), suggesting that overall genetic variation in this pathway contributes to lung cancer risk. In addition, the IL1B -1060TT (i.e. -511TT) genotype was associated with increased lung cancer risk compared with the CC genotype [odds ratio (OR) = 2.27, 95% confidence interval (CI) = 1.05-4.91]. The IL8RA Ex2+860 GC or CC (OR = 0.27, 95% CI = 0.11-0.67), ICAM1 Ex2+100 AT or TT (OR = 0.39, 95% CI = 0.18-0.88) and IL12A Ex7+277 GA or AA (OR = 0.43, 95% CI = 0.22-0.84) genotypes were associated with decreased lung cancer risk. The protective effect of the IL8RA variant was stronger among subjects with high cumulative smoky coal use (> or = 130 tons) (OR = 0.11, 95% CI = 0.03-0.44; P(interaction) = 0.03). In conclusion, genetic variation in immunoregulatory genes may play an important role in the development of lung cancer in this population.