The WWOX gene is considered to be a tumor-suppressor gene which encodes a protein (Wwox) implicated in various types of solid human cancers. It has been shown that overexpression of WWOX in human tumors promotes apoptosis in vitro and suppresses tumor growth in vivo. Recently, we investigated the effects of WWOX overexpression in vitro and observed marked growth arrest in human leukemia cells; however, the underlying mechanism(s) for this effect is unknown. The present study aimed to elucidate the primary mechanism(s) underlying WWOX-mediated apoptosis in human leukemia. We traced the interactions between WWOX and its associated factors p73 and p53 after WWOX overexpression was induced in Jurkat and K562 cells. Our data revealed that p73 participates in WWOX-mediated apoptosis in Jurkat and K562 cells through binding with Wwox in the cytoplasm without a nuclear-cytoplasmic translocation.