Weight gain and increased adipose tissue are undesired side-effects frequently associated with the treatment of olanzapine (Zyperaxa) and other atypical neuroleptics in schizophrenic patients. The suggested mechanism for the olanzapine-induced weight gain is its serotoninergic (5-HT) and histaminergic receptor antagonistic activity. Fluoxetine (Prozac), a selective serotonin reuptake inhibitor (SSRI), enhances central 5-HT activity and was reported to lower food intake and leptin levels. The aim of the study was to evaluate the effect of combined administration of fluoxetine and olanzapine on weight gain and on hormonal profile in schizophrenic patients. 30 schizophrenic patients (21 men and 9 woman) during first episode of schizophrenia were studied. Patients received olanazapine (10mg/day) with either fluoxetine (20mg/day) or placebo for eight week. Body weight was registered and blood samples were taken before initiation, and at the end of the study for the determination of prolactin, cortisol, TSH, Leptin, and serum serotonin. Our data showed that olanzapine treatment caused a significant increase in body weight in both placebo and fluoxetine co-treated patients, the increase in body weight was accompanied by a significant increase in leptin levels (from 4.3 to 10.0ng/ml and form 5.1 to 11.2ng/ml) in the olanzapine and olanzapine + fluoxetine groups respectively. Serum serotnin levels slightly increased after olanzapine, and significantly decreased after the combined olanzapine+ fluoxetine treatment. No significant difference was registered in prolactin, cortisol, and TSH levels. Our data suggest that SSRI are ineffective in preventing olanzapine-induced increased body weight gain, and that this undesired side -effect is independent of olanzapine 5HT2A receptor antagonistic activity.