Involvement of phosphatidylinositol 3-kinase/Akt-1 in cell survival and proliferation of multiple myeloma (MM) has been well established. In this study, we demonstrate that homoharringtonine (HHT), an antileukemic drug first isolated from the Chinese evergreen Cephalotaxus harringtonia, induces significant cytotoxicity in dexamethasone-sensitive and -resistant and chemotherapy-sensitive MM cell lines in a time and dose-dependent manner. HHT also triggers apoptosis in chemotherapy-resistant patient's myeloma cells. Contrary to dexamethasone, the cytotoxicity of HHT on myeloma is independent of interleukin-6. The mechanism of HHT cytotoxicity is related to down-regulation of Akt phosphorylation/activation and various target genes of Akt including nuclear factor kappa B, XIAP, cIAP and cyclin D1. Moreover, in vivo antitumor activity of HHT is demonstrated in RPMI8226 myeloma xenograft model. Importantly, an additive effect of antitumor is confirmed in the myeloma cells treated with HHT and bortezomib concomitantly with inhibition of phosphorylated Akt. Together, these findings obtained with HHT should give useful insights into a novel antimyeloma chemotherapy.