We found an increased lymphocyte proliferation after stimulation with an antigen "cocktail" in 49 schizophrenic patients and 37 patients suffering from affective psychosis, compared with 45 healthy control subjects. On the basis of this and other findings such as increased numbers of CD3+ and CD4+ cells, an increased ratio of CD4+/CD8+ cells, and a reduced level of suppressor cell activity in schizophrenia and endogenous depression, we investigated the influence of the human leukocyte antigen-Class I (HLA-A, HLA-B, HLA-C) system on the altered immune function and evaluated the relationship to immune function of a family history of psychiatric disorders. A cluster analysis of cases with regard to the HLA-Class I antigens was first performed in a group of 133 healthy control subjects, and two immunogenetically different clusters were found; then 86 patients (49 schizophrenics, 37 affective psychoses) for whom immune functional data were available were assigned to the two HLA-I clusters that had been determined in the control subjects. Analyses of variance (ANOVAs) showed no differences in immune function between the two clusters. With respect to the cluster assignment and the family history of psychiatric diseases, a two-way ANOVA revealed significant differences in the lymphocyte response to the antigen cocktail, in the number of CD8+ cells, and in one suppressor cell assay. When patients were compared by ANOVA on the basis of family history of psychiatric disorder, patients with a positive family history showed a significantly higher number of CD4+ cells and a higher CD4+/CD8+ ratio. Moreover, certain HLA genes, especially HLA-A1, HLA-B8, HLA-B16, and HLA-C2 seemed to be related to the immune function and/or to the immune function and the family history.