Sodium valproate, a histone deacetylase inhibitor, decreases the secretion of soluble Fas by human osteosarcoma cells and increases their sensitivity to Fas-mediated cell death. Effects of valproic acid (VPA), a histone deacetylase inhibitor, on the susceptibility to cell death induced by agonistic anti-Fas antibody were examined using four human osteosarcoma cell lines.Cell growth, secretion of soluble Fas, expression of cell-surface Fas, and sensitivity to Fas-mediated cell death were examined using cell proliferation assay, flow cytometry, enzyme-linked immunosorbent assay, and agonistic anti-Fas antibody, respectively.VPA suppressed the growth of all the four osteosarcoma cell lines and the secretion of soluble Fas from these cells. VPA showed no or slight suppressive effect on the expression of cell-surface Fas in the four osteosarcoma cell lines, but increased the sensitivity of three of four osteosarcoma cell lines to Fas-mediated cell death.VPA enhances the susceptibility of human osteosarcoma cells to Fas-ligand-induced cell death by decreasing the secretion of soluble Fas and increasing the sensitivity to Fas-mediated cell death.