We report that in Jurkat T cells or freshly isolated T lymphocytes, physiological concentrations of high– molecular weight sulfated polysaccharides such as heparin, heparan sulfate, and dextran sulfate significantly increased the percentage of cell death induced by Fas IgM agonistic antibody. The phenomenon was caspase dependent and P53 independent and correlated with an increased accessibility of cell surface Fas receptors. We also observed that the Fas IgM agonistic antibody–dependent formation of sodium dodecyl sulfate (SDS)–resistant large structures containing Fas receptor was decreased in the presence of heparin-like agents. In contrast, the different agents had no effect when cell death was triggered by FasL, the natural ligand of Fas that does not generate SDS-resistant forms of Fas. Interestingly, the synergistic effect of heparin-like agents toward Fas IgM agonistic antibody–mediated cell death abolished Hsp27 antiapoptotic activity but did not alter much the protection generated by Bcl-2 expression.