Background: Complement C3 is an emerging risk factor for coronary heart disease (CHD) and is particularly increased in the metabolic syndrome. A direct effect of smoking on structure and function of complement C3 has been suggested. Hypothesis: Smoking behavior may affect the cardiovascular risk that is associated with plasma complement C3. Methods: The association between plasma C3 and CHD was studied in the CODAM (Cohort on Diabetes and Atherosclerosis Maastricht) study population (n=562, 61% male) with examination of effect modification by smoking. Results: The overall prevalence of CHD was 23.3%. Higher plasma C3 levels were associated with a higher CHD prevalence, and there was a significant interaction with heavy smoking (p=0.01). In never & light smokers, the univariate OR for CHD per 1 s.d. (0.33 g/L) increase in C3 was 1.09 [95% confidence interval (CI) 0.85-1.41] (p=0.505) whereas in heavy smokers it was 2.05 [1.43-2.93] (p<0.001). The association in the group of heavy smokers remained significant (OR 2.38 [1.54-3.68], p<0.001) after adjustment for traditional risk factors for cardiovascular disease and also after further adjustment for other cardiometabolic risk factors, i. e. the metabolic syndrome, CRP and insulin resistance (HOMA2IR) (OR C3 between 2.16 and 2.29, all p <= 0.001). Conclusion: Human plasma complement C3 is associated with prevalent CHD, but only in heavy smokers, and this association is independent of important metabolic cardiovascular risk factors. (C) 2010 Elsevier Ireland Ltd. All rights reserved.