In addition to its orexigenic properties, ghrelin has been shown to modulate the secretory pattern of pituitary hormones, and it may exert direct effects on peripheral organs such as the gonads and endocrine pancreas. To study possible interactions among ghrelin, glucose homeostasis, and the reproductive system, we investigated 10 obese women with polycystic ovary syndrome (OB-PCOS) in comparison with 10 age- and body mass index-matched obese subjects (OB). Plasma levels of insulin, glucose, androgens, and ghrelin were measured at baseline condition and after 7 months of therapy (hypocaloric diet + metformin or placebo). Plasma ghrelin levels were lower in OB-PCOS than in OB (P < 0.05). A strong negative correlation between ghrelin and androstenedione levels was found in both populations at baseline (OB-PCOS: P < 0.01; OB: P < 0.001) and after therapy (OB-PCOS: P < 0.01; OB: P < 0.05), whereas no correlation was found between ghrelin and other androgens. In both groups, the markers of insulin resistance in fasting and stimulated conditions (glucose/insulin ratio, homeostasis model insulin resistance index, homeostasis model applied to the oral glucose tolerance test) demonstrated decreased insulin sensitivity. However, a negative correlation between plasma ghrelin and all these markers was observed only in the OB-PCOS group (P < 0.05). Accordingly, a negative correlation between ghrelin variation and treatment-induced changes of the glucose/insulin ratio, HOMA-R, and HOMA(OGTT) was observed only in the OB-PCOS group (P < 0.05). In conclusion, OB-PCOS women have lower ghrelin levels than those expected based on the presence of obesity. Only in OB-PCOS, ghrelin negatively correlates with insulin sensitivity. In addition, regardless of the presence of PCOS, a marked negative correlation exists between ghrelin and androstenedione levels, suggestive of an interaction between ghrelin and steroid synthesis or action.