Novel antipsychotic drugs (APDs) have enhanced therapeutic actions compared to ‘typical’ APDs. However,clinical studies indicate that some induce marked weight gain. We attempted to model this effect in female Wistar rats given olanzapine chronically at 4 mg/kg b.i.d (4.5 h between injections). Such rats showed marked weight gain, which was statistically significant after only a single day of treatment, although weight gain increased up to a plateau after 10 days of treatment. Cessation of treatment led to rapid weight loss, which was significant after a single day of withdrawal. The weight gain observed was characterized by marked individual differences. As some clinical reports suggest that novel APD-induced weight gain is most pronounced in patients with the lowest body weight, we examined the relationship between weight gain and baseline body weight. However, we observed no significant relationship between baseline body weight and weight gain. The observation that olanzapine can induce weight gain rapidly in rats, in conjunction with the observation of marked individual differences in weight gain, suggests that patients at risk of developing weight gain might be detectable early in treatment. Furthermore, the finding that weight gain is rapidly reversible suggests that patients at risk of weight gain could be switched to APDs with less pronounced tendencies to induce weight gain. The study of APD-induced weight gain in rodents may provide insights into the nature, causes, and treatments for, novel APD-induced weight gain in the clinic. However, it remains to be determined how closely rodent models mimic the clinical situation and whether the mechanism(s) involved in the weight gain we have observed are the same as those involved in the clinical use of these drugs.