BACKGROUND Few studies have examined the relationship between cigarette smoking and novel risk factors for cardiovascular disease in a general population or have included a biochemical marker of current smoking. OBJECTIVE To examine the relationship between cigarette smoking and serum C-reactive protein, fibrinogen, and homocysteine levels. METHODS Cross-sectional study. METHODS The U.S. general population. METHODS 4187 current smokers, 4791 former smokers, and 8375 never-smokers 18 years of age or older who participated in the Third National Health and Nutrition Examination Survey conducted between 1988 and 1994. METHODS Serum C-reactive protein levels were categorized as detectable (2.2 to 9.9 mg/L) or clinically elevated (> or =10 mg/L), and fibrinogen and homocysteine levels were defined as elevated if in the 85th percentile or greater (11.1 micromol/L and 12.7 mmol/L, respectively). RESULTS After adjustment for traditional cardiovascular disease risk factors, cigarette smoking was related to elevated levels of C-reactive protein, fibrinogen, and homocysteine. Compared with never smoking cigarettes, self-reported current cigarette smoking was associated with a C-reactive protein level in the detectable (odds ratio, 1.66 [95% CI, 1.40 to 1.97]; P < 0.001) or clinically elevated (odds ratio, 1.98 [CI, 1.57 to 2.51]; P < 0.001) ranges, with elevated levels of fibrinogen (odds ratio, 2.15 [CI, 1.65 to 2.80]; P < 0.001) and homocysteine (odds ratio, 2.10 [CI, 1.62 to 2.74]; P < 0.001). There were positive and significant dose-response relationships between measures of cigarette smoking (cigarettes per day, pack-years, and serum cotinine levels) and elevated levels of novel risk factors. CONCLUSIONS These findings suggest that inflammation and hyperhomocysteinemia may be important mechanisms by which smoking promotes atherosclerotic disease.