Smoking and interleukin-6 (IL-6) are major factors in inflammation. The aim of this study was to investigate whether or not the IL6 -634C/G polymorphism (rs1800796) and its interaction with smoking influence serum C-reactive protein (CRP) concentrations. The subjects were 347 Japanese male employees of a transit company. CRP and conventional cardiovascular risk factors were evaluated. IL6 -634C/G polymorphisms were genotyped by allelic discrimination using fluorogenic probes and the 5' nuclease assay. The mean values of CRP were significantly higher in current smokers than in nonsmokers after adjustment for age, body mass index (BMI), systolic blood pressure, total cholesterol, log triglycerides, high-density lipoprotein cholesterol (HDL-C), fasting glucose, and drinking habit (p=0.011). Comparison of three genotypes revealed significant interaction between smoking and the IL6 -634C/G genotype manifested by CRP concentrations (p=0.007) after the adjustments cited above. After stratification by smoking status, CRP differed significantly among IL6 -634C/G genotypes groups in nonsmokers (p=0.010, p for trend=0.007), whereas no significant difference was found in current smokers. Comparison between -634C/C and C/G+G/G groups revealed also a significant interaction between smoking and the IL6 -634C/G genotype (p=0.007). These findings suggest that the impact of the -634G allele on CRP elevation is greater in nonsmokers than in current smokers. Since gene-environment interactions have been insufficiently examined, further studies are required to clarify their effect on inflammation, including CRP elevation.