HDAC inhibitors (HDACis) represent a class of anticancer agents including suberoylanilide hydroxamic acid (SAHA, Vorinostat), which has shown a strong antitumor effect, both in vitro and in vivo. Induction of apoptotic genes is an important pathway of SAHA cytotoxic mechanism of action and it has been largely described that SAHA induces sensitization of cell death receptor-resistant breast cancer cells to apoptosis. In this study, we investigated the activation of some apoptotic genes which could be responsible for the in vivo antitumor potency of SAHA in a model of human breast cancer. We found that the apoptotic gene pattern induced by SAHA in the MDA-MB-231 cell line involves the upregulation of some molecules belonging to the TNF superfamily. In particular, we demonstrated that the upregulation of the CD137 receptor/ligand system correlates with a synergistic cytotoxic effect when MDA-MB-231 cells are treated with the combination of SAHA and soluble CD137 receptor. To our knowledge, this is the first study to indicate that this member of the TNF superfamily, CD137, is modulated by SAHA treatment in breast cancer cells, suggesting that the combination of SAHA with this TNF-related receptor could be a new therapeutic approach for the treatment of tumors.