OBJECTIVES: Studies evaluating the association between statins and colorectal cancer (CRC) have used various methods to address bias and have reported mixed findings.  We sought to assess the association in a large cohort of residents in Emilia-Romagna, Italy, using multiple methods to address different sources of confounding.  We also sought to explore potential effect measure modification by sex. METHODS: We conducted a retrospective population-based new-user cohort study using the 2003–2010 longitudinal healthcare database of Emilia-Romagna, Italy. This comprehensive database contains information on healthcare services rendered to the population, including hospital, outpatient pharmacy and specialty data. We identified all initiators of statins; initiators of glaucoma medications served as the comparison group to account for confounding by healthy user bias. We followed patients longitudinally to identify CRC cases in hospital discharge data. We used multivariable Cox regression analyses to adjust for confounding by CRC risk factors and we conducted a sensitivity analysis using propensity score matching. RESULTS: Among 215,963 statin initiators, we observed 1870 cases of CRC, reflecting a crude incidence rate of 222.2 cases per 100,000 person-years. After multivariable adjustment, initiators of statins had a lower incidence rate of CRC as compared to initiators of glaucoma drugs (hazard ratio, 0.79; 95% CI, 0.69 to 0.90).  In sex-stratified analyses we observed a protective effect in men (hazard ratio, 0.77; 95% CI, 0.67 to 0.88) but not in women (hazard ratio 0.96; 95% CI, 0.82 to 1.1).  Results were similar in propensity score analyses.   CONCLUSIONS: After adjusting for observed risk factors, statin initiation versus glaucoma drug initiation was associated with a reduced risk of CRC in men but not in women. While this study is subject to many limitations, it corroborates a previous study that found sex differences in the association between statins and CRC.