INTRODUCTION: Treatment with some antipsychotic drugs may result in excessive body weight gain which can have detrimental effects on patient compliance, morbidity and mortality. The aim of the present study was to investigate the effect of atypical antipsychotic drugs on dietary macronutrient selection, body weight, body composition and biochemical parameters related to obesity in female rats. MATERIALS AND METHODS: Forty pair-housed, adult female hooded-Lister rats (250 +/- 5 g) were habituated to three diets containing principally protein, fat, or carbohydrate in a home cage self-selection paradigm. Olanzapine (2 mg/kg), risperidone (0.5 mg/kg), ziprasidone (2.5 mg/kg), or vehicle was injected intraperitoneally once daily for 22 days; food selection, water intake, and body weight were recorded daily, while body composition and plasma hormones (insulin, glucose, nonesterified free fatty acid, total cholesterol, glycerol, triacylglycerol, leptin, and prolactin) were analyzed at the end of the study. RESULTS: Only olanzapine significantly increased body weight and food intake. Macronutrient selection was significantly altered after olanzapine and risperidone treatment (increased protein and decreased fat preference). Only olanzapine increased carcass fat content. Locomotor activity was significantly reduced in all treatment groups. Both olanzapine and risperidone significantly increased plasma prolactin. Olanzapine was without effect on any other biochemical parameter measured. Ziprasidone significantly reduced plasma leptin and nonsignificantly reduced NEFA, while risperidone significantly reduced fasting plasma glucose. CONCLUSION: This study supports our previous work demonstrating weight gain and increased feeding behavior induced by olanzapine and could have important implications for enhancing our understanding of the mechanisms by which olanzapine and other atypical antipsychotics induce weight gain in the clinic.