OBJECTIVES: The use of standard immediate release metformin (MIR) two or three times daily has been associated with gastrointestinal adverse events (GIAE). Metformin XR (MXR) is a once a day extended release formulation that offers a potential benefit of a decrease in the frequency of GIAE and increased adherence rates in patients diagnosed with Type 2 Diabetes Mellitus (T2DM). This systematic review identifies published evidence regarding the efficacy, safety, and adherence of MXR relative to MIR in the treatment of T2DM. METHODS: We searched relevant bibliographic databases, internet and grey literature, and included all studies with an analytical or observational design. We assessed the quality of all selected studies following the Cochrane Collaboration recommendations. When possible, we calculated the mean global effect of MXR vs. MIR for clinical outcomes. RESULTS: The search identified 81 studies of which 10 met inclusion/exclusion criteria for analysis. The quality of these 10 studies was generally poor. Efficacy results of 187 patients were included in a meta-analysis that estimated the mean difference with respect to baseline measurements. Glycosylated hemoglobin (HbA1c) control, fasting plasma glucose and lipid control was similar in both treatments (MD=0.01 CI95%=-0.38-0.41; MD=0.32 CI95%=-0.25-0.89; MD=0.16 CI95%=-0.23-0.54, respectively). The frequency of GIAE was meta-analyzed using data from 1,045 patients, and the global Relative Risk was estimated (RR= 0.97; CI95%=0.80-1.19). Patients treated with MXR experienced a significantly lower incidence of nausea (RR=0.82; CI95%=0.46-1.95) and dyspepsia (RR=0.64; CI95%=0.29-1.43) than patients on MIR. Adherence was reported in two studies, showing that patients treated with MXR have a significantly higher adherence to treatment than MIR cohorts. CONCLUSIONS: Treatment once a day with MXR tablets has comparable efficacy to a two or three times daily dosage with MIR. MXR offers the benefit of increased adherence to treatment, and a lower frequency of nausea and dyspepsia compared to MIR.