In this report we described a psychotic episode associated with dexfenfluramine use in a patient with major depression. The patient never had any psychotic disorder before the current episode. This episode could have been a rare adverse effect of dexfenfluramine alone or the result of an interaction between dexfenfluramine and doxepin, a tricyclic antidepressant agent that inhibits the reuptake of norepinephrine into the nerve terminals at the synaptic level. Considering the size and the high motivation of the target population, the pharmacologic actions, drug interactions, and adverse effect profile of dexfenfluramine need to be reevaluated. Even more important is the responsibility of all physicians to closely follow their patients after prescribing a newly approved drug.