Background: Although diabetes (DM) is associated with a worse colorectal cancer (CRC) prognosis, metformin (M) use has been associated with improved overall and CRC-specific survival in several prior studies. We examined the impact of M use on overall survival (OS) in patients with type 2 DM and CRC among US veterans while adjusting for treatment, stage and diabetic severity, offering the largest cohort study examining this issue to date. Methods: There were 21,352 patients with CRC were diagnosed between 2001 and 2008 in the US Veterans Health Administration. OS was compared across four groups: patients without DM (n=16,355); patients with DM on M (n= 2,038); patients with DM on anti-DM medications other than M (n=2,136); and patients with DM not on anti-DM medication (n=823). Multivariate Cox proportional hazards models were used to estimate the association between M use, DM and OS while adjusting for age, race, stage, body mass index, HbA1C, comorbidity index, and cancer treatment. Results: Median survival was 61 months in non-diabetics, 67 months in metformin users, 45 months in users of other diabetic medications, and 51 months in diabetics not on anti-DM medication. HbA1C levels were 6.9%, 6.8%, and 6.2% in patients with DM on metformin, other, or no anti-DM medication, respectively. In the subset of CRC patients with DM, those patients taking M had a 21% decrease in the risk of death compared to patients with diabetes taking anti-DM medications other than M (HR_adj 0.79; 95% CI 0.73-0.86, p=<0.001), while diabetic patients not on any anti-DM medications had a 13% decrease in risk of death (HR_adj 0.87; 95% CI 0.78-0.97, p=0.02). No interaction between M and BMI was observed (p=0.86). In the entire cohort, patients with DM on anti-DM medications other than M had a statistically significant increase in risk of death compared to non-diabetics (HR_adj 1.26; 95% CI 1.19-1.33, p=<0.0001). However, patients with DM on M had similar OS as compared to non-diabetics (HR_adj 1.05; 95% CI 0.99-1.12, p=0.11), as did patients with DM not on anti-diabetic medication (HR_adj1.08; 95% CI 0.99-1.18, p=0.07). Conclusions: Among diabetics with CRC, M use is associated with improved survival as compared to the use of other medications. Metformin may reduce the survival disadvantage associated with DM among CRC patients.