Cross-sectional associations between leukocyte count and sociodemographic and cardiovascular risk factors were investigated in 14,679 participants aged 45-64 years in the Atherosclerosis Risk in Communities Study carried out in four US communities in 1986-1989. Leukocyte count was strongly associated with present or past history of cigarette smoking and was higher in males than in females and in white subjects than in black subjects. Among never smokers, no sex differences were evident after adjustment for other risk factors. Race-associated differences were substantially reduced after other factors were taken into account in multivariate analyses. In never smokers, leukocyte count was higher in those who reported poor health, and it was inversely associated with high density lipoprotein cholesterol, forced expiratory volume at 1 second, physical activity, and, among whites, height and socioeconomic indicators. It was directly associated with indices of body weight and body fat, heart rate, blood pressure, hemoglobin, platelet count, uric acid, fasting insulin and glycemia, triglycerides, fibrinogen, antithrombin III, protein C, factors VII and VIII, and von Willebrand factor. The associations of leukocyte count with cardiovascular risk factors may either represent manifestation of subclinical disease or suggest that leukocyte count is part of the causal chain leading to atherosclerosis. Alternatively, the relation of leukocyte count to cardiovascular disease may be confounded by risk factors and thus be noncausal.