Mouse monoclonal antibodies (MAbs) directed against the HIV-1 gp120 envelope protein were screened for their reactivity with intracellular antigens expressed in normal uninfected monocytes by indirect immunofluorescence and immunoblotting. Some of these MAbs reacted with the nuclei of normal uninfected cells, producing three main staining patterns by indirect immunofluorescence. Western blot analysis showed that these monoclonal antibodies recognize peptides of various molecular weights present in nuclei preparations of normal monocytes. Reactivity with peptides of similar molecular weight was also detected in sera from both HIV-infected individuals and patients with systemic lupus erythematosus. This evidence for antigenic similarities between HIV-1 gp120 and nuclear antigens represents a novel example of molecular mimicry of self-antigens by HIV envelope proteins, which supports the involvement of mechanisms of autoimmunity in HIV disease pathogenesis through recruitment of autoimmune responses to self-structures by HIV antigens.