BACKGROUND: White blood cell count is an independent risk factor for cardiovascular disease. Several lifestyle and metabolic factors such as cigarette smoking and obesity are known to be associated with an elevated white blood cell count. However, the joint effect of cigarette smoking and obesity on white blood cell count has not yet been fully described. METHODS: We explored the joint effect of cigarette smoking and obesity on white blood cell count using multiple logistic regression analyses after adjusting for confounding variables in a population-based, cross-sectional study of 416,065 Korean adults. RESULTS: Cigarette smoking and body mass index have a dose-response relationship with a higher white blood cell count, but no synergistic interaction is observed between them (men, P for interaction=0.797; women, P for interaction=0.311). Cigarette smoking and body mass index might have an additive combination effect on high white blood cell count. Obese male smokers were 2.36 times more likely and obese female smokers 2.35 times more likely to have a high white blood cell count when compared with normal body mass index non-smokers. CONCLUSION: Cigarette smoking and body mass index are independently associated with an elevated white blood cell count in both men and women.