d-Fenfluramine (2.5 mg/kg i.p.) caused marked hypophagia in food-deprived rats and significantly increased medial hypothalamic extracellular 5-hydroxytryptamine (5-HT) as indicated by in vivo microdialysis. When the drug was given after the 5-HT synthesis inhibitor p-chlorophenylalanine (150 mg/kg per day x 3) the hypophagic response was unimpaired but dialysate 5-HT concentration no longer rose. The d-fenfluramine metabolite d-norfenfluramine (1.5 mg/kg i.p.) caused slightly greater hypophagia than the parent drug and completely blocked feeding in animals pretreated with p-chlorophenylalanine, but dialysate 5-HT was increased in neither circumstance. The results provide evidence against mediation of the hypophagic effects of d-fenfluramine and d-norfenfluramine by increased availability of 5-HT to receptors.