Based on the similar effects that HIV-1 gp41 like human type I interferons (IFN-alpha and -beta) upregulated MHC expression and inhibited lymphocyte proliferation, we compared amino acid sequences of gp41 and human type I interferons (IFN-alpha and -beta), and found sequence-similarity existing between the immunosuppressive domain (aa583-599, LQARILAVERYLKDQQL) of HIV-1 gp41 and human IFN-alpha (region aa117-129) and IFN-beta (region aa128-134); besides, the immunosuppressive domain of HIV-1 gp41 shows sequence-homology with bovine and murine IFN-alpha and IFN-beta in the same region. We examined polyclonal antibodies to human IFN-alpha and IFN-beta respectively and found that both antibodies could recognize rsgp41 from two different sources. The polyclonal antibody to IFN-beta could bind to the immunosuppressive peptide (ISP, aa583-599, LQARILAVERYLKDQQL) of HIV-1 gp41, only when the ISP was coupled with carrier-protein, and inhibit, if preincubated with rsgp41, binding of rsgp41 to human H9 (T cells), Raji (B cells), and U937 (monocyte cells) completely. The polyclonal antibody to IFN-alpha could partially inhibit the binding of rsgp41 to U937 and Raji. These results indicate that a common immunological epitope exists between HIV-1 gp41 and human type I interferons.