Factors that aid survival of prostate cancer cells in the presence of the various categories of cytotoxic cytokines present in tumors in vivo are largely unknown. Osteoprotegerin (OPG) is a decoy receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that inhibits TRAIL-induced apoptosis. In relation to this activity, we hypothesized that the ability to produce OPG by prostate cancer cells would confer a survival advantage on these cells. In this study we have demonstrated that high levels of OPG are produced by the hormone-insensitive prostate cancer cell lines PC3 and Du145, whereas the hormone-sensitive cell line LNCaP produced 10-20-fold less OPG under the same conditions. A strong negative correlation was observed between levels of endogenously produced OPG in the medium and the capacity of TRAIL to induce apoptosis in cells that produced high levels of OPG. The antiapoptotic effect of OPG was reversed by coadministration of 100-fold molar excess of receptor-activator of nuclear factor-kappaB ligand, another protein that selectively binds OPG. These observations suggest that prostate cancer-derived OPG may be an important survival factor in hormone-resistant prostate cancer cells.