BACKGROUND Sibutramine is a reuptake inhibitor of 5-hydroxytryptamine and noradrenaline, being developed as a treatment for obesity. OBJECTIVE To investigate the effect of sibutramine on glucose homeostasis in obese-hyperglycaemic insulin-resistant ob/ob mice. METHODS Sibutramine 5 mg/kg once daily was administered orally to ob/ob mice for six weeks. RESULTS Sibutramine treatment decreased body weight gain by 12% without a significant overall change in daily food intake. Sibutramine reduced the hyperinsulinaemia by 31%, and lowered plasma non-esterified fatty acids (NEFA) by 17%. Basal plasma glucose concentrations were not significantly altered by sibutramine, but glucose concentrations fell more rapidly after an i.p. glucose challenge, despite lower insulin concentrations. The rate of insulin-induced glucose disappearance was increased by 10% during sibutramine treatment. First administration of sibutramine, 5 mg/kg, did not acutely alter basal plasma glucose, insulin or NEFA concentrations in ob/ob mice, although NEFA concentrations were raised after 24 h. CONCLUSIONS The results indicate that chronic administration of sibutramine can reduce weight gain, lower NEFA concentrations, decrease hyperinsulinaemia and ameliorate the insulin resistance of ob/ob mice.