Diabetes treatments were related with either an increased or reduced risk of cancer. There is ongoing debate about a potential protective action of metformin. To summarize evidence on the association between metformin and risk of cancer and cancer mortality in patients with diabetes. MEDLINE and EMBASE (January 1966-April 2012). We selected randomized studies comparing metformin and other hypoglycaemic agents and observational studies exploring the association between exposure to metformin and cancer. Outcomes were cancer mortality, all malignancies and site-specific cancers. Of 25307 citations identified, 12 randomized controlled trials (21,595 patients) and 41 observational studies (1,029,389 patients) met the inclusion criteria. In observational studies there was a significant association of exposure to metformin with the risk of cancer death 6 studies, 24,410 patients, OR:0.65, 95%CI: 0.53-0.80, all malignancies 18 studies, 561,836 patients, OR:0.73, 95%CI: 0.61-0.88, liver 8 studies, 312,742 patients, OR:0.34; 95%CI: 0.19-0.60 colorectal 12 studies, 871,365 patients, OR:0.83, 95%CI: 0.74-0.92, pancreas 9 studies, 847,248 patients, OR:0.56, 95%CI: 0.36-0.86, stomach 2 studies, 100701 patients, OR:0.83, 95%CI: 0.76-0.91, and esophagus cancer 2 studies, 100694 patients, OR:0.90, 95%CI: 0.83-0.98. No significant difference of risk was observed in randomized trials. Metformin was not associated with the risk of: breast cancer, lung cancer, ovarian cancer, uterus cancer, prostate cancer, bladder cancer, kidney cancer, and melanoma. Results suggest that Metformin might be associated with a significant reduction in the risk of cancer and cancer-related mortality. Randomized trials specifically designed to evaluate the efficacy of metformin as an anticancer agent are warranted.