Background: Two promoter polymorphisms, -174G>C and -572C>C, in the interleukin-6 (IL-6) gene have been associated with circulating IL-6 levels although results are conflicting. Smoking is also known to be associated with increased levels of systemic markers of inflammation. We investigated whether smoking would interact with IL-6 promoter polymorphisms in determining circulating levels of inflammatory markers and its consequence to oxidative stress. Methods and Results: Healthy male subjects (n=644) were recruited and genotyped. The G/G genotype (n=26) of the -572C>G in nonsmokers (n=376) was associated with higher IL-6 (P=0.028), fibrinogen (P=0.007) and ox-LDL (P=0.006) than those with C/C (n=209) or C/G (n=141). Results were similar for nonsmokers and smokers (n=268), but in smokers, the -572G/G genotype was associated with a greater difference in levels of IL-6 (P=0.031), fibrinogen (P=0.001), ox-LDL (P=0.037) and PGF2慣 (P=0.050). IL-6 had positive relations with CRP, fibrinogen, ox-LDL and PGF2慣. There was no evidence of an effect of -572C>G genotype on CRP levels in nonsmokers, however, this polymorphism was associated with a highly significant effect on CRP in smokers (P<0.001) (genotype-smoking interaction P=0.04, adjusted for age, BMI and IL-6). The C allele frequency at the -174 promoter region of IL-6 was very rare (<0.01) in this study. Conclusion: Our results suggest that IL-6 -572C>G has a greater response over time to the inflammatory effects of smoking and this may result in smokers having higher oxidative stress in subjects with G/G compared to C/C or C/G.