Parkinsonism presents a notoriously discouraging therapeutic problem, since no treatment heretofore employed has significantly altered the course of the disease. Recent work with antihistamines suggests that certain of these compounds may have value in the Parkinsonian syndromes.Promethazine chemically resembles chlorpromazine, which is known to be active upon the extrapyramidal system and related areas. It was decided to investigate the potential value of promethazine since it was believed that the compound might also affect the extrapyramidal structures but in a different way.Twelve patients with advanced Parkinsonism (associated with cerebral arteriosclerosis in 5, of the postencephalitic type in 2, and of the idiopathic type in 5) received promethazine in conservative dosage by mouth for periods totaling 2 to 16 weeks.Among the patients with Parkinsonism, 11 (91%) showed some evidence of improvement, which was not limited to motor activity alone but in most cases involved other physical and behavioral spheres in which there had been severe deterioration. One-third showed clinical change of an unusual degree.Further study of promethazine in Parkinsonian syndromes and the associated mental disorders is suggested, especially for aged and arteriosclerotic patients.