The addition of monosialoganglioside GM1 to serum-free culture medium efficiently and specifically inhibited CD4 antigen expression on normal T lymphocytes from peripheral blood or thymus as well as on cells from H9 and Molt-3 lines; other molecules such as CD3, CD2 and CD8 were not affected. Subsequent addition of fetal calf serum or bovine and human serum albumin blocked GM1 action on CD4 expression, most likely through the formation of ganglioside-albumin complexes. Removal of GM1 from the medium was followed by the prompt reappearance of CD4 on the cell surface. GM1 treatment of H9 and Molt-3 cells greatly reduced HIV-1 infectivity, which was evaluated by reverse transcriptase activity levels in culture supernatants and p24 detection on target cells. GM1 also inhibited syncytial formation in Molt-3 cells even when treatment was initiated 24h after infection. The GM1 effect on HIV-1 infectivity, however, was not long-lasting since removal of the compound was followed by a rapid increase in viral replication, probably due to CD4 re-expression and HIV-1 propagation from a few initially infected cells.