This study employed immunocytochemistry to visualize the neurotoxic effects of methylenedioxyamphetamine hydrochloride (MDA) on serotonergic projections to brainstem structures. Separate groups of animals were injected twice a day, for 4 consecutive days, with: saline; MDA (40 mg/kg/day); or fluoxetine hydrochloride (10 mg/kg) prior to each injection of MDA. In agreement with previous reports, MDA produced a pronounced loss of 5-HT immunoreactivity in the forebrain, most notably in neocortex and hippocampus. However, our results revealed that MDA also produced a loss of 5-HT fibers in brainstem that was as severe as that seen in any region of forebrain. Regions most severely affected included: superior colliculus; superior olivary complex; trigeminal sensory complex and vestibular nuclei. The brains of animals treated with MDA demonstrated a relative absence of fine 5-HT axon terminals within these forebrain and brainstem regions, while thicker axonal elements were still present. The neurotoxic effects of MDA on serotonergic projections to forebrain and brainstem were completely blocked by the prior administration of the 5-HT reuptake inhibitor, fluoxetine. It was suggested that the denervation of the superior colliculus, superior olive and vestibular nuclei could alter visually guided eye movements and the vestibulo-ocular reflex while the loss of serotonergic inputs to the trigeminal sensory complex might be expected to alter tactual reflexes.