Phenylalanine-containing peptides from CD4 were synthesized based on chemical similarity with active CD4(81–92)-benzylated peptides. The synthetic peptide FYIFFVEDQKEEDD) blocked the binding of gp120 to CD4 and inhibited 50% μ human immunodeficiency virus (HIV)-induced syncytia formation at a concentration (1C50) of 40–50 μM and HIV p17 expression with an 1C50 of 67 μM. The peptide is not toxic to cells in vitro. Moreover, acute toxicity studies carried out in Swiss mice showed the peptide to be nontoxic at a dose of 2.000 mg kg. This phenylalanine-substituted CD4 peptide may prove to be useful in the treatment of AIDS.