Loss of normal immune homeostasis occurs in acquired immune deficiency syndrome (AIDS). We evaluated patients at the University of Cincinnati and New York University Medical Centers for serologic evidence of autoimmune changes. Specifically, tests for antinuclear and organ-specific antibodies by immunofluorescence, antisperm and anti-seminal plasma antibodies, rheumatoid factor by latex and sensitized sheep cell agglutination techniques, anti-polyadenosine (poly A), and single-stranded DNA antibodies were performed in human immunodeficiency virus (HIV) antibody-positive sera. A parallel study of mitogen responsiveness was performed and showed inhibition of response by AIDS and AIDS-related complex (ARC) sera. In spite of evidence of polyclonal B-cell activation, hyperglobulinemia, and the presence of antibodies to many infectious agents, as well as the known cellular immune abnormalities, the patients tested had a striking absence of these autoantibodies. The only major difference noted from normal controls, was a low but significant level of antibody binding to poly A. The autoimmune connective tissue diseases were not observed in this group of patients.