Background White cell count (WCC) is a clinical marker of inflammation. Data are limited regarding the association of total and differential WCC with risk of mortality, and its role related with smoking and body mass index (BMI). Methods A total of 14 433 participants (4150 men; 10 283 women; average age 47.3 +/- 11.8 years) from the Dutch European Prospective Investigation into Cancer and Nutrition-Netherlands cohort were included. The associations between prediagnostic total WCC and its subtypes and risk of all-cause, cancer and cardiovascular disease (CVD) mortality were assessed. The role of WCC related with smoking and BMI on mortality was further explored. Multivariate Cox regression models were performed to estimate the HR and 95% CI. Results After an average follow-up of 15.8 years, a total of 936 death cases were identified (466 cancer; 179 CVD; 291 other causes). Statistically significant graded associations between total WCC, and counts of lymphocytes, monocytes, neutrophils and eosinophils and risk of total mortality were observed. These associations were more apparent in current smokers. Strong associations for all-cause mortality or cancer mortality were observed in subjects with BMI >= 25 kg/m(2), ever smoking and elevated WCC (HR 3.92, 95% CI 2.76 to 5.57; HR 3.93, 95% CI 2.30 to 6.72). WCC partly mediated the associations between smoking or BMI and all-cause mortality. Conclusions Prediagnostic WCC and its subtypes are associated with all-cause, cancer and CVD mortality risk. It may play a partially mediate role on the association between smoking or obesity and mortality.