Human immunodeficiency virus type 1 (HIV-1) transmembrane glycoprotein 41 (gp41) contains an immunosuppressive domain (Env amino acids 583-599). Previous studies by us and others using recombinant soluble gp41 (rsgp41; amino acids 539-684) and immunosuppressive peptide (1SP; a gp41 peptide, amino acids 583-599) have shown that HIV-1 gp41 by the immunosuppressive domain could bind to several proteins on human T, B and monocyte cell lines, and also to normal human peripheral blood mononuclear cells. In this study we demonstrated that HIV-1 rsgp41 could inhibit spontaneous cell proliferation of human T cell lines H9 and Jurkat, B cell lines Raji and Daudi, monocyte cell line U937, but could not inhibit cell proliferation of human fibroblast cell line HEF and green monkey kidney cell line Cos-1. HIV-1 rsgp41 could inhibit also concanavalin A (Con A)-, phytohaemagglutinin (PHA)- and tetanus toroid (TT)-induced cell proliferation of normal human peripheral blood lymphocytes, with 50% inhibition at a concentration of 8 mu M, but could not inhibit pokeweed mitogen (PWM)-induced lymphocyte proliferation. Furthermore, recombinant soluble gp36 of HIV-2 like HIV-1 rsgp41 could inhibit Con A-, but not PWM-induced lymphocyte proliferation. These results indicate that HIV-1 gp41-induced inhibition of proliferation is selective in so far as the effect of PWM is not altered while the effects of several other stimuli are.