Inflammation may be linked to the pathogenesis of colorectal cancer. However, two conflicting observational results were recently reported on the relationship between the inflammatory marker C-reactive protein (CRP) and the risk of colorectal cancer. Few epidemiologic studies have examined the association between inflammatory markers and the risk of colorectal cancer. We prospectively examined the mortality and incidence risk for colon and rectal cancers among 424,419 Koreans (108,907 men and 315,512 women). The subjects were 40 to 95 years of age and from the Korean Cancer Prevention Study (KCPS) cohort. All subjects received medical examination from the National Health Insurance Corporation in 1993 and 1995. The maximum follow-up period was 10 years, and the follow-up periods began in January 1, 1994 and ended in December 31, 2003. An elevated white blood cell count (WBC) was associated with a higher mortality risk of colon cancer (highest versus lowest quartile: men, 1.55, 95% CI 1.10-2.18, p for trend = 0.0014; women, 1.51, 95% CI 1.12- 2.03, p for trend = 0.0049). Similarly, an elevated WBC was associated with a higher incidence risk of colon cancer (highest versus lowest quartile: men, 1.38, 1.09-1.76, p for trend = 0.0017; women, 1.46, 95% CI 1.20-1.78, p for trend= 0.0003). A positive linear trend was also observed in non- smokers. There was no significant association between WBC and the risk of rectal cancer. Our findings demonstrate that an elevated WBC is associated with an increase in both the mortality and incidence rates of colon cancer. These results support our hypothesis that inflammation increases the risk of colon cancer.