Long-term treatment with tricyclic antidepressant drugs (TCAs) can induce excessive body weight gain in a significant proportion of patients. Such weight gains, which appear to be largely independent of clinical improvement, are in many cases severe enough to interfere with continuation of treatment. In efforts to model this effect in experimental animals, seven experiments were performed in which two commonly used TCAs, amitriptyline and desipramine, were administered chronically to rats. Despite manipulations of drug dosages (2.5 mg-17 mg/kg), route of administration (intraperitoneal, subcutaneous, oral; daily injections vs. continuous release from osmotic pumps), diet composition and palatability (regular Purina Chow pellets or powder with or without added high fat and high carbohydrate sources; high vs. low protein diets) and animal sex and housing conditions (single vs. group housing), chronic TCA treatment was never observed to increase daily food intake or rates of body weight gain. Desipramine treatment invariably caused decreased food intake and weight loss. Amitriptyline treatment either caused no change in food intake and body weight or slightly reduced levels in comparison to vehicle-treated controls. However, both amitriptyline- and desipramine-treated rats showed a potentiation of acute caloric intake after a single systemic injection of the glucoprivic agent 2-deoxy-D-glucose. These results are considered against the background of human clinical observations. Possible reasons for the differences between human and animal data are discussed.