This report describes that gp41, the transmembranous envelope protein of HIV, is able to inhibit monocyte chemotaxis (measured as FMLP-induced polarization). To study the presence of such immunosuppressive HIV env proteins in the circulation of HIV-infected men, fractions were prepared from serum via ultrafiltration, yielding molecules with a relative Mr of 25-50. These fractions inhibited FMLP-induced polarization of normal human monocytes, while similar fractions of HIV-uninfected men did not. A monoclonal antibody (MoAb) to gp41 was able to adsorb the serum factor responsible for this inhibitory activity. This demonstration of the presence of a gp41-like factor in the circulation of HIV-infected men exerting immunosuppressive activities might have implications for the understanding of the pathogenesis of AIDS, as well as for the selection of HIV-encoded proteins for putative vaccines.