OBJECTIVES: The aim of the review was to compare the efficacy and safety of vildagliptin versus glimepiride as add-on therapy to metformin in patients with type 2 diabetes mellitus. METHODS: The analysis was performed in accordance with the rules of systematic review, based on the Cochrane Collaboration (Cochrane Reviewer’s Handbook) guidelines and the Health Technology Assessment Agency in Poland recommendations. Literature search strategy was performed within the main medical databases: Medline, Cochrane Library, EMBASE, Biomed Central and CRD. RESULTS: one study of high quality was identified according to predefined selection criteria. The trial evaluated fifty-two-week effectiveness of vildagliptin plus metformin versus glimepiride plus metformin. The analysis disclosed non inferior efficacy of intervention and comparator in HbA1c reduction. The change in fasting plasma glucose was also comparable between groups. Patients in vildagliptin group more frequently reached a target HbA1c level of < 7% without hypoglycaemia (50.9% of participants) than patients in glimepiride group (44.3% of participants). Furthermore vildagliptin was more efficient in body weight reduction; WMD =  -1.79 (95% CI: -2.11; -1.47). The risk of hypoglycaemia episodes was higher within glimepiride therapy; RR = 0.10 (95% CI: 0.07; 0.16). Vildagliptin treatment resulted in lower incidence of adverse events, serious adverse events and discontinuation because of adverse events (respectively 74.5%, 7.1%, and 4.8% in vildagliptin group versus 81.1%, 9.5%, and 7.7% in glimepiride group). The risk of cardiovascular complications was higher in comparative group but it was not statistically significant.  Dizziness, fatigue, asthenia, tremor, hyperhidrosis and hunger were significantly less frequent in vildagliptin group. CONCLUSIONS: Vildagliptin as add-on therapy to metformin is more efficient and safer technology than glimepiride combined with metformin in the treatment of type 2 diabetes mellitus.