OBJECTIVES There are currently many kinds of sulphonylurea agents taken as the first-line drugs for patients with diabetes. As the second-generation sulfonylureas, we try to explore the comparative efficacy and safety of sustained-release glipizide and gliclazide for type 2 diabetes mellitus. METHODS A systematic review of randomized controlled trials (RCTs) was conducted. PUBMED, EMBASE, The Cochrane Library, three Chinese Databases (CBM, CNKI, and VIP) , as well as the citations or reference lists were searched from their inception to July 31, 2008. The pharmaceutical companies were contacted for unpublished studies. Trial selection, quality assessment and data extraction were performed by two reviewers independently. We pooled the trial data using the random-effect model and explored the heterogeneity by the pre-specified variables. RESULTS Only two trials (n=190) compared the extended-release glipizide with gliclazide based on the treatment of metformin or acarbose and diet control. The quality of included trials was poor. Only randomized trials were mentioned without detailed information on the methods of generating randomization sequences, concealment allocation, and blinding. The durations of follow-up(12 weeks) were too short to obtain the long-term effects of the diabetes-related morbidity and mortality. Both sustained-release glipizide and gliclazide had significantly reduced HbA1c , fasting and postprandial blood glucose from baseline to the end of treatment. However, there was no significant difference between groups, including the changes of HbA1c (weighted mean difference=0.13, 95%CI=-0.21 to 0.46), fasting blood glucose (-0.07 [-0.67, 0.52]), and postprandial blood glucose (1.40 [-0.80, 3.60]).There is similar safe profiles in hypoglycemia, changes of lipid and body weight, and liver and renal functions. CONCLUSIONS The limited evidence showed that both sustained-release glipizide and gliclazide are effective in glucose control with similar effects and safe profile. More high-quality RCTs are expected to explore the effects of different sulfonylurea agents.