Patients infected with human immunodeficiency virus have a variety of presentations including fevers, lymphadenopathy, rash, renal dysfunction, and neurologic and hematologic disorders. Many of these features are also seen in patients with systemic lupus erythematosus (SLE). Herein are described five patients ultimately diagnosed as having acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) in whom the differential diagnosis included SLE because of multi-system disease and autoimmune phenomena, especially positive antinuclear antibodies. Serum samples from 151 consecutive patients with AIDS or ARC were examined and 19 with low titer-positive antinuclear antibodies were found (17 at 1:20 and two at 1:160). These observations suggest that SLE and human immunodeficiency virus infection may share clinical and serologic features.