Inflammation has been shown to be a risk factor for several chronic diseases. Few epidemiologic studies have examined the relationship between markers of inflammation and cancer. The current study included 7,674 Second National Health and Nutrition Examination Survey (NHANES II) participants, 30 to 74 years of age, between 1976 and 1980. Mortality follow-up through December 31, 1992 was assessed using the National Death Index and Social Security Administration Death Master File. A graded association between higher WBC and higher risk of total cancer mortality was observed [highest versus lowest quartile (relative risk [RR] 2.23; 95% confidence interval [CI], 1.53-3.23)] after adjusting for age, sex, and race. After further adjustment for smoking, physical activity, body mass index, alcohol intake, education, hematocrit, and diabetes, WBC remained significantly associated (P trend = 0.03) with total cancer mortality [highest versus lowest quartile (RR 1.66; 95% CI, 1.08-2.56)]. In stratified analyses, increased WBC was associated with higher risk of non-lung cancer (P trend = 0.04), but not lung cancer (P trend = 0.18). Among never smokers, a 1 SD increase in WBC (2.2 x 10(9) cells/L) was associated with greater risk of total (RR 1.32; 95% CI, 1.05-1.67) and non-lung (RR 1.30; 95% CI, 1.03-1.63) cancer mortality. These findings support the hypothesis that inflammation is an independent risk factor for cancer mortality. Additional studies are needed to determine whether circulating levels of inflammatory markers are associated with increased risk of incident cancer.