The appetite-suppressant, fenfluramine (d,l-F) has been used for several decades to treat obesity. Dexfenfluramine (d-F), the d-enantiomer of d,l-F, was approved in 1996 for long-term administration. Subsequently, these drugs were voluntarily withdrawn due to reports of adverse effects on heart valves. So far, the evidence regarding the serotonergic action of d,l-F and d-F has relied on animal-based experiments. We used human platelets as neuronal models to assess the serotonergic action of both d,l-F, d-F and the main metabolite of d-F, d-norfenfluramine (d-norF). This was evaluated using a sensitive method that assesses platelet shape change (PSC) as expressed by an increase in median platelet volume (MPV). Human platelets increased their MPV in response to d-norF. This action was probably mediated via serotonin (subtype 2) receptors because a specific antagonist blocked it. This is the first demonstration, using human tissue, of the serotonergic action associated with the administration of d-F.