The relationship of white blood cell count (WBC) to fatal and nonfatal coronary heart disease (CHD) incidence and all-cause and cancer mortality was assessed in a subset of participants in the Multiple Risk Factor Intervention Trial (MRFIT). For this group of 6,222 middle aged men, total WBC count was found to be strongly and significantly related to risk of CHD, independent of smoking status. Change in WBC count from baseline to the annual examination just prior to the CHD event was found to be a significant and independent predictor of CHD risk. For each decrease in WBC count of 1,000/cu mm the risk for CHD death decreased 14%, controlling for baseline WBC count and other CHD risk factors (smoking, cholesterol level, diastolic blood pressure). The WBC count was strongly related cross-sectionally to cigarette smoking and smoking status as indicated by serum thiocyanate concentration. Smokers on average had a WBC count of 7,750/cu mm compared with 6,080/cu mm for nonsmokers. The WBC count was also significantly associated with cancer death, independent of reported smoking and serum thiocyanate levels.