Leptin is a 167 amino acid protein encoded by the obesity gene that is synthesized in adipose tissue and interacts with receptors in the hypothalamus linked to the regulation of appetite and metabolism. It is known to suppress appetite and increase energy expenditure. Cyproheptadine is a piperidine antihistamine that increases appetite through its antiserotonergic effect on 5-HT2 receptors in the brain. Although both leptin and cyproheptacline are effective in controlling appetite, their interaction has not been addressed in clinical studies. This study evaluated serum leptin concentrations in patients who received cyproheptadine to treat a variety of disorders. Sixteen patients aged 7 to 71 years (mean, 26.25 years) were given cyproheptacline 2 to 6 mg/day for a minimum of 7 days. Body weight was measured and blood samples were obtained at baseline and after 1 week of treatment. Serum leptin levels were determined by leptin radioimmunoassay. The mean body weight at baseline (52.59 kg) did not differ significantly from that at 1 week after treatment (52.84 kg; P >.05), but the mean leptin level after 1 week of treatment with cyproheptacline (3.14 ng/mL) was 14.2% higher than that at baseline (2.75 ng/mL; P <.05). This increase may suggest that both leptin and cyproheptacline may affect appetite via similar receptors and that cyproheptacline does not impair leptin activity through these receptors. Further study will be necessary to clarify this relationship.