We investigated the role of some gp120 peptides on the apoptosis induction in malignant T cell lines. We took advantage of recent findings reporting that three major regions of gp120 are important for CD4 binding. They consist of residues 256-262 in the C2 domain, residues 368-389 in the C3 domain, and residues 421-457 in C4 domain. We used a peptide from C2 domain (aa 250-263) the homologous major histocompatibility complex (MHC) class II peptide (aa 135-155) and three peptides from domain C4 (aa 414-434; 419-430; 428-445). We selected for this study the following human cell lines: CEM and Jurkat, two lymphoblastoid CD4-positive T cell line and U937, a myelomonocytic CD4 positive cell line. We demonstrated that the CD4-positive T cell lines, in the presence of gp120 250-263 peptide and DR 135-155 peptide, can be induced to accelerate apoptosis, while no effect in apoptosis induction was observed in the presence of 414-424 gp120 peptide. Interestingly, we have shown by fluorescence study, that the small sequence 414-419 must be responsible for the inhibition of binding of gp120 to the CD4 molecule. Indeed while 414-424 gp120 peptide is very efficient in CD4-gp120 binding inhibition, no effect is observed in the presence of either 419-430 or 428-445 peptide.