During the budding process, human immunodeficiency virus (HIV) acquires several cellular proteins from the host. Thus, antibodies against self antigens found in sera patients with autoimmune disorders may cross react with host-derived or the HIV-specific proteins gp120 and gp41 on the viral envelope and probably neutralize HIV infection. To verify this hypothesis, 88 sera from HIV negative patients suffering from systemic lupus erythematosus (SLE) and other autoimmune disorders were analysed for cross reacting antibodies against HIV-1 by Western blot and FACS analysis indicating that antibodies cross-react with epitopes expressed on HIV infected or non-infected cells. Virus capture assays revealed that HIV-1(IIIB) was directly recognized by 60% of sera from patients with autoimmune disorders. Sera were also tested in HIV neutralization assays with stimulated T cells. Reduction of the viral load by patient sera correlated with their reactivity in Western blot analysis. Complement further enhanced the reduction of viral titres, although no complement-mediated lysis was observed. These data suggest a possible protective role of auto-antibodies against HIV infection in lupus patients.