Because of a potent action of angiotensin converting enzyme (ACE) to degrade substance P (SP) and an association of the insertion/deletion (I/D) polymorphism of the ACE gene with ACE activity, an association between the SP level and the ACE I/D polymorphism were examined using 20 human postmortem brain samples. The results showed a significant association between the polymorphism and SP levels in the basal ganglia and substantia nigra, where both ACE and SP concentrate, and a higher SP level in the subjects with the DD genotype than in those with the II genotype, with an intermediate level in heterozygotes. Associations of the polymorphism with schizophrenia and affective disorders were also investigated in 292 unrelated Japanese schizophrenics, 65 patients with affective disorders, and 579 controls. The D allele was significantly more frequent in the patients with affective disorders than in the controls (p < .02), and the DD genotype was significantly more frequent in the patients with affective disorders than in the controls (p < .002). There is no significant difference in the frequencies of the allele and the genotype between the controls and schizophrenics. These results suggest that the ACE I/D polymorphism is one of the genetic factors for an interindividual variability of brain SP levels, and that the ACE polymorphism may contribute to the susceptibility to affective disorders.