Sequence-comparison indicates existing sequence-similarity between receptor-binding regions of human type 1 IFNs (IFN-alpha, -beta and -omega) and HIV-1 gp41. Previous findings had suggested that the increased levels of antibodies against human IFN-alpha and -beta in HIV-1-infected individuals are associated with a common epitope on gp41, IFN-alpha and -beta. To clarify the relationship between human type I interferon and HIV-1 gp41 and the protective mechanism of an IFN-alpha-vaccine, we prepared antisera against human IFN-alpha, -beta and HIV-1 gp41, and examined crossreaction of these antisera and their inhibition of gp41 binding to its binding protein p45. Mouse antisera against IFN-alpha and -beta could recognize HIV-1 recombinant soluble (aa539-684) and gp41 immunosuppressive peptide (ISP, aa583-599), while normal mouse sera (pre-immune sera) did not. Mouse antisera to rsgp41 crossreacted with IFN-alpha and -beta. Besides, mouse antisera to IFN-alpha and beta, like mouse anti-rsgp41 antiserum, could inhibit gp41-binding to its putative cellular receptor protein p45, while normal mouse serum did not. These results indicate that antibodies crossreacting with gp41 ISP, IFN-alpha and -beta, could be induced by this common immunological epitope in vivo.