Background &Aims: Endogenous hyperinsulinemia in the context of type 2 diabetes mellitus is potentially associated with an increased risk of colorectal cancer. We aimed to determine whether insulin therapy might increase the risk of colorectal cancer among type 2 diabetes mellitus patients. Methods: We conducted a retrospective cohort study among all patients with a diagnosis of type 2 diabetes mellitus in the General Practice Research Database from the United Kingdom. We excluded patients with < 3 years of colorectal cancer free database follow up after the diabetes diagnosis as well as those insulin users who developed colorectal cancer after < 1 year of insulin therapy. The remaining insulin users and the noninsulin using type 2 diabetic patients were followed for the occurrence of colorectal cancer. Hazard ratios (HR) were determined in Cox proportional hazard analysis. A nested case control study was conducted to perform multivariable analysis and to determine a duration response effect. Results: The incidence of colorectal cancer in insulin users (n = 3160) was 197 per 100,000 person years, compared with 124 per 100,000 person years in type 2 diabetes mellitus patients not receiving insulin (n = 21 ,758). The age and sex adjusted HR of col orectal cancer associated with ≥1 year of insulin use was 2.1 (95%CI: 1.2-3.4, P=0.005). The positive association strengthened after adjusting for potential confounders. The multivariable odds ratio associated with each incremental year of insulin therapy was 1.21 (95%CI: 1.03-1.42, P = 0.02). Conclusions: Chronic insulin therapy significantly increases the risk of colorectal cancer among type 2 diabetes mellitus patients. Background & Aims: Endogenous hyperinsulinemia in the context of type 2 diabetes mellitus is potentially associated with increased risk of colorectal cancer. We aimed to determine whether insulin therapy might increase the risk of colorectal cancer among type 2 diabetes mellitus patients. Methods: We conducted a retrospective cohort study among all patients with a diagnosis of type 2 diabetes mellitus in the General Practice Research Database from the United Kingdom. We excluded patients with <3 years of colorectal cancer free database follow up after the diabetes diagnosis as well as those insulin users who The remaining insulin users and the noninsulin using type 2 diabetic patients were for the occurrence of colorectal cancer. Hazard ratios (HR) were determined in Cox proportional hazard analysis. A nested case control study was conducted to perform multivariable analysis and determine a duration response Results: The incidence of colorectal cancer in insulin users (n = 3160) was 197 per 100,000 person years, compared with 124 per 100,000 person years in type 2 diabetes mellitus patients not receiving insulin (n = 21, 758). The age and sex adjusted HR of colorectal cancer associated with ≥1 year of insulin use was 2.1 (95% CI: 1.2-3.4, P = 0.005). The positive association strengthened after adjusting for potential confounders. The multivariable odds ratio associated with each incremental year of insulin therapy was 1.21 (95% CI: 1.03-1.42, P = 0.02). Conclusions: Chronic insulin therapy significantly increases the risk of colorectal cancer among type 2 diabetes mellitus patients.