To compare the effects of sulfonylureas and metformin versus metformin on lipid profiles, blood pressure, and adverse events. PubMed, EMbase, Chinese BioMedical Literature on disc, China National Knowledge Infrastructure, VIP database, and Wanfang database were searched for randomized controlled trials (RCTs), from inception to August 2012. Key outcomes were low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), total cholesterol (TC), blood pressure (BP), hemoglobin A1c (HbA1c), fasting insulin, and adverse events. Twenty RCTs were included in the analysis. Compared to metformin, the combination therapy of sulfonylureas and metformin slightly reduced HDL-C [-0.03, 95 % CI (-0.06, -0.01)] and HbA1c (-0.79, 95 % CI -0.96 to -0.63). However, it showed little effects on LDL-C, TG, TC, and BP. Glipizide plus metformin significantly increased fasting insulin [2.33, 95 % CI (1.94, 2.73)]. Hypoglycemia and nervous system side events were more frequent among patients treated with sulfonylureas plus metformin than metformin alone (RR = 6.79, 95 % CI 3.79-12.17; RR = 1.27, 95 % CI 1.03-1.57; respectively), but less in digestive symptoms (RR = 0.75, 95 % CI 0.67-0.84). Combination therapy with sulfonylureas and metformin may be more effective than metformin alone in improving HbA1c and reducing gastrointestinal reactions. But it had disadvantage of decreasing HDL-C, increasing the risk of hypoglycemia and nervous system side events.