OBJECTIVES: Basic scientific evidence suggests that statins inhibit the growth of colon-cancer cell lines, and secondary analyses of some randomized clinical trials suggest that they reduce the risk of colorectal cancer. However, evidence from several observational studies has been conflicting on whether the risk of colorectal cancer is reduced in statin users. We sought to assess the association between statin use and the rate of colorectal cancer in a large cohort of residents in Emilia-Romagna, Italy. METHODS: We conducted a population-based cohort study using the longitudinal health care database of Emilia-Romagna, Italy, a region with approximately 4.2 million inhabitants. This comprehensive database contains information on all health care services rendered to the population, including hospital, outpatient pharmacy and specialty data. We identified all initiators of statins; initiators of glaucoma medications served as a comparison group. Colorectal cancer cases were identified by hospital discharge data. Multivariable logistic regression analyses were used to adjust for confounding. RESULTS: Patient characteristics were similar in both groups, but statin initiators (50,534) were prevalently male, were slightly younger, and used hospital services more frequently than glaucoma medication initiators (78,361). During a maximum of 3 years of follow-up, the incidence rate of colorectal cancer was lower in the statin users than in the glaucoma medication users (0.49% vs. 0.79%; Relative Risk, 0.69, 95% CI, 0.52 to 0.92). The adjusted odds ratio for statin use compared with nonuse was 0.67 (95% CI, 0.57 to 0.79). CONCLUSIONS: The use of statins was associated with a 33% relative reduction in the risk of colorectal cancer after adjustment for observable risk factors. Because the analysis may not have accounted for every potential confounder, further investigation of the overall benefits of statins in preventing colorectal cancer is warranted.