BACKGROUND: The immune system and inflammation are implicated in the pathogenesis of cancer. Prospective studies linking biomarkers of inflammation with cancer incidence and mortality have been inconclusive. METHODS: To determine whether there is an independent association of white blood cell (WBC) count with incident cancer in postmenopausal women, a prospective cohort study was performed at 40 US clinical centers involving 143,748 postmenopausal women aged 50 to 79 years who were free of cancer at baseline and were enrolled in the Women's Health Initiative. The main outcome measures were incident invasive breast, colorectal, endometrial, and lung cancer. RESULTS: In multivariate models, there was a graded association of WBC count with incidence of all 4 types of cancer. Compared with the lowest quartile of WBC count (2.50-4.79x10(9) cells/L), women with a WBC count in the upper quartile (6.80-15.00x10(9) cells/L) had a statistically significantly higher risk of invasive breast cancer (hazard ratio [HR], 1.15; 95% confidence interval [CI], 1.04-1.26), colorectal cancer (HR, 1.19; 95% CI, 1.00-1.41), endometrial cancer (HR, 1.42; 95% CI, 1.12-1.79), and lung cancer (HR, 1.63; 95% CI, 1.35-1.97). The findings were similar when cancers that occurred during the first 2 years of follow-up were excluded. Statistically significant associations remained for invasive breast cancer and endometrial cancer when the analyses were limited to nonsmokers. The WBC count was also statistically significantly associated with breast cancer, lung cancer, and overall cancer mortality. CONCLUSION: Postmenopausal women with higher WBC counts have a higher risk of incident invasive breast, colorectal, endometrial, and lung cancer, as well as a higher risk of breast, lung, and overall cancer mortality.