OBJECTIVE We aimed to investigate the effect of ghrelin antagonist (D-Lys3) GHRP-6 on the treatment of ovariectomy-induced obesity as compared to hormone replacement therapy with estradiol. METHODS Twenty eight rats were divided into four groups: control sham operated (C), ovariectomized non-treated (OVX), ovariectomized+estradiol-treated (OVX+E) groups, and ovariectomized+ghrelin antagonist-treated group (OVX+GA). Rats were allowed free water and commercial standard diet ad libitum for 5 weeks after surgery. Body mass index (BMI) was determined at the beginning and the end of the experiment. Rats were sacrificed by decapitation and blood samples were collected for measurements of serum lipid profile, insulin, and glucose levels. Gastrocolic omental fat (GCOF) was removed and weighed. RESULTS Ovariectomy was accompanied with a significantly higher body weight, food intake, BMI, GCOF, serum total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), glucose, insulin, and homeostatic model assessment - insulin resistance (HOMA-IR), with a significant decrease in high density lipoprotein-cholesterol (HDL-C) and triglycerides (TGs) in comparison with C group. Estradiol reversed the ovariectomy-induced changes except that of TGs. Administration of ghrelin antagonist was effective in treating the ovariectomy-induced obesity as evidenced by normalization of body weight, food intake, BMI, and GCOF weight, serum levels of insulin, glucose, HOMA-IR, and HDL-C. The serum levels of TC, LDL-C and TGs were improved but did not reach the control values. CONCLUSIONS Although estradiol succeeded in the prevention of almost all ovariectomy-induced disturbances, it had a potential cardiovascular risk due to a marked increase in serum TGs. Ghrelin antagonist was effective in ameliorating ovariectomy-induced obesity, so it may be used as a promising treatment for postmenopausal obesity, irrespective of hormonal replacement.