Background: The aim of this study was to evaluate the effect of berberine administration on metabolic syndrome, insulin sensitivity, and insulin secretion. Methods: A randomized, double-blind, placebo-controlled clinical trial was carried out in 24 patients with a diagnosis of metabolic syndrome. Glucose and insulin levels after a dextrose load were measured. Triglycerides and high-density lipoprotein cholesterol concentrations at baseline were also measured. Twelve patients received berberine hydrochloride (500mg) three times daily before meals for 3 months. The remaining 12 patients received placebo. Area under the curve (AUC) of glucose and insulin, total insulin secretion, first-phase of insulin secretion, and insulin sensitivity were assessed. Results: After berberine administration, patients had a remission of 36% (P=0.037) in the presence of metabolic syndrome and a significant decrease in waist circumference in females (1064 vs. 103 +/- 3cm, P<0.05), systolic blood pressure (SBP) (123 +/- 7 vs. 115 +/- 9mmHg, P<0.01), triglycerides (2.4 +/- 0.7 vs. 1.4 +/- 0.5mmol/L, P<0.01), area under the curve (AUC) of glucose (1182.1 +/- 253.6 vs. 1069.5 +/- 172.4mmol/l, P<0.05), AUC of insulin (92,056 +/- 72,148 vs. 67,407 +/- 46,441pmol/L, P<0.01), and insulinogenic index (0.78 +/- 0.69 vs. 0.62 +/- 0.46, P<0.05), as well as an increase in the Matsuda index (2.1 +/- 1.0 vs. 3.1 +/- 1.6, P<0.01). Conclusions: Administration of berberine leads to remission of metabolic syndrome and decreases in waist circumference, SBP, triglycerides, and total insulin secretion, with an increase in insulin sensitivity.