A number of risk factors have been proposed for the development of neuroleptic malignant syndrome, but these have not been subjected to controlled study. To address this problem, we performed a case-control study comparing 18 patients with neuroleptic malignant syndrome and 36 matched neuroleptic-treated control patients with no known history of the syndrome to identify potential risk factors. Patients with neuroleptic malignant syndrome displayed significantly greater psychomotor agitation, received significantly higher doses of neuroleptics at greater rates of dosage increase, and received a greater number of intramuscular injections than controls.