From a review of the clinical literature, the authors determined that the medical symptoms of neuroleptic withdrawal occurred more frequently with neuroleptics having potent anticholinergic effects than with those having weak anticholinergic actions. When antiparkinsonian agents were not simultaneously withdrawn, there was a striking difference between these two categories of neuroleptics. Experiments with mice showed that withdrawal of haloperidol, a neuroleptic with weak anticholinergic effects, produced subsensitivity (depression of locomotor activity and seizure thresholds) to the cholinergic effects of physostigmine. These findings support the theory that the medical side effects of neuroleptic withdrawal are due to rebound cholinergic hypersensitivity associated with the anticholinergic actions of these drugs, rather than being related to their dopamine-blocking activity.