Both slow-release (SR) and regular-release (RR) metformin were effective in the treatment of type 2 diabetes mellitus. We compare the efficacy, safety, and effects on serum adipocytokines and inflammatory markers of both regimens in patients with type 2 diabetes mellitus. A prospective, randomized, double-blind study enrolled 55 patients with type 2 diabetes mellitus, which were randomly assigned to receive either metformin SR or RR (at a maximal dosage of 2000 mg/d for 12 weeks). Glycosylated hemoglobin A1c (HbA1c), fasting plasma glucose, adipocytokines, C-reactive protein, and insulin resistance and pancreatic beta-cell function were measured before and after treatment. Significant decreases (P<.001) in mean HbA1c and fasting plasma glucose levels were observed in each group. However, the mean changes in HbA1c from baseline to end point in the 2 groups were not significantly different. Changes in metabolic parameters were similar except that a decreased total cholesterol level was observed in the metformin RR group. Neither regimen treatment had any influence on insulin resistance, but metformin RR improved beta-cell function. Neither regimen had an effect on serum adipocytokines or inflammatory markers. Once-daily metformin SR was as safe and effective as metformin RR in type 2 diabetic patients. Neither dosage form affected serum adipocytokines and inflammatory markers.