BACKGROUND: Plasma levels of tumor necrosis factor (TNF)-alpha and of C-reactive protein (CRP) are elevated in smokers. Previous studies failed to show an association between the G-308A polymorphism in the promoter region of the TNF-alpha gene and coronary artery disease (CAD). We investigated whether smoking would interact with the TNF-alpha G-308A polymorphism in determining plasma levels of TNF-alpha and CRP. METHODS: Study participants with a complete data set in terms of smoking and the TNF-alpha G-308A polymorphism were 300 middle-aged male and female industrial employees. After excluding 24 irregular smokers, analyses were performed on 198 "non-smokers" (life-long non-smokers or subjects who quit smoking >6 months ago) as compared to 78 "regular smokers" (subjects currently smoking >3 cigarettes/day). All subjects had a fasting morning blood draw to measure plasma levels of TNF-alpha and CRP by high-sensitive enzyme-linked immunosorbent assays. RESULTS: The cardiovascular risk factor adjusted analysis regressing log-transformed CRP levels against smoking status, genotype, and smoking-status-genotype interaction revealed a significant main effect for smoking status (F1,250 = 5.67, p = .018) but not for genotype (F1,250 = 0.33, p = .57). The interaction-term between genotype and smoking status was not significant (F1,250 = 0.09, p = .76). The fully adjusted model with plasma TNF-alpha failed to show significant main effects for smoking and genotype, as well as for the smoking-status-genotype interaction. CONCLUSIONS: The findings suggest that the TNF-alpha G-308A polymorphism does not mediate the effect of smoking on plasma CRP levels. It remains to be seen whether other genetic polymorphisms along the inflammatory pathway may modulate vascular risk in smokers.