Excessive body weight gain is an undesirable side effect of prolonged administration of antipsychotic drugs (AP), which affects health and interferes with treatment compliance. It has been suggested that hyperprolactinemia-induced endocrine and metabolic abnormalities, particularly in the gonadal steroids, might be involved in the development of this type of weight gain. To test this hypothesis, reproductive hormones, cortisol, dehydro-epiandrosterone-sulfate (DHEA-S), thyroid hormones, and body weight gain were assessed in 18 patients (9 men, 9 women) with mental disorders receiving AP who had been medication-free for at least 3 months before the study, and in 27 placebo-treated subjects (10 men, 17 women). In women, hormones were evaluated during several phases of the menstrual cycle. A significant weight gain was observed in men but not in women. Under AP administration, women displayed significantly lower serum levels of estradiol and progesterone, whereas in men the levels of free testosterone and DHEA-S were significantly lower than in controls. Hyperprolactinemia was observed in both sexes. The levels of follicle-stimulating hormone in women and luteinizing hormone in men were significantly elevated by treatment, thus suggesting that the functioning of the hypothalamus-pituitary gonads was preserved. In men, such an endocrine profile resembles that observed in subjects with primary obesity. Women under AP administration were found to be relatively hyperandrogenic because of decreased serum estradiol levels, whereas women with primary obesity are known to display actual increased levels of androgens. These endocrine abnormalities may contribute to the excessive weight gain observed after AP treatment, and these could be the target of novel pharmacological treatments.