Based on our findings that HIV-1 (human immunodeficiency virus type 1) soluble gp41 (sgp41; amino acids 539-684) bound to human T, B, and monocyte cells and enhanced major histocompatibility complex (MHC) class I and II antigen expression on Raji cells, we examined the effect of HIV-1 sgp41 on the surface expression of MHC I and II, ICAM-1, and CD4 molecules on human H9 and U937 cells. Flow cytometry (FACS) analysis demonstrated that sgp41 selectively enhanced MHC class I expression by about 75% on H9 cells and by about 85% on U937 cells, while the ICAM-1 expression was increased by about 70% only on H9 cells and remained unaltered on U937 cells; other molecules, such as MHC class II and CD4, remained unaltered. By comparison, alpha-, beta-, and omega-interferons, but not gamma-interferon, showed similar effects as sgp41 on the expression of MHC class I and ICAM-1 on H9 and U937 cells. The results suggest that HIV-1 gp41 may have a biological function that is involved in the regulation of human MHC class I and ICAM-1 expression.