An association between elevated white blood cell (WBC) count and coronary heart disease (CHD) mortality has been previously observed. However, the relationship between WBC count and CHD mortality independent of cigarette smoking and the possible interaction between WBC count and smoking remains unclear. We examined the association between WBC count and CHD mortality with Cox regression analyses of data from 8914 adults, aged 30-75, in the NHANES II Mortality Study (1976-1992). Covariates included age, sex, race, education, physical activity, smoking status, hypertensive status, total serum cholesterol, body mass index, hematocrit, and history of cardiovascular disease, stroke, and diabetes. During 17 follow-up years, there were 548 deaths from CHD (ICD-9 410-414) and 782 deaths from diseases of the heart (ICD-9 390-398, 402, 404, 410-414, 415-417, 420-429). Mean WBC count (x10(9) cells/L) was greater among persons who died from CHD (7.6 vs 7.2, P <.001). Compared to persons with a WBC count <6.1, persons with a WBC count > 7.6 were at increased risk of death from CHD (relative risk = 1.4, 95% confidence interval = 1.1-1.8) after adjustment for smoking status and other CVD risk factors. Similar results were observed among nonsmokers (RR = 1.4, 95% CI = 0.9-2.0). These results suggest that higher WBC counts are a predictor of CHD mortality independent of the effects of smoking and other traditional CVD risk factors, which may indicate a role for inflammation in the pathogenesis of CHD. Additional studies are needed to determine whether interventions to decrease inflammation can reduce the risk for CHD associated with elevated WBC.