Background: Allergic conditions are associated with reduced risk of several malignancies. We hypothesized that blood eosinophil count, a marker for allergic disorders, is inversely associated with the risk of colorectal cancer (CRC) in the Atherosclerosis Risk in Communities prospective cohort. To our knowledge, the association between blood eosinophil count and cancer risk has not been investigated before. Methods: Relative eosinophil and total leukocyte counts were measured in blood at baseline. Absolute eosinophil counts were calculated by multiplying relative count by the total leukocyte count. Proportional hazards regression provided HRs and 95% CIs of CRC in relation to eosinophil count. Results: From 1987-2006, 242 incident CRC cases (187 colon and 56 rectal) occurred in 10,675 initially cancer-free participants. In a multivariate-adjusted model, HRs were 1.0, 0.70 (95% CI: 0.50-0.98) and 0.58 (95% CI: 0.40-0.83) across tertiles of absolute eosinophil count (P trend = 0.003). A similar inverse association was observed for relative eosinophil count. Age, sex, race, or smoking status did not modify associations. Conclusions and Impact: We observed an inverse association between blood eosinophil count and CRC risk. This novel finding supports the hypothesis that allergies are protective for CRC, as an increased eosinophil count correlates with allergy in the developed world.