Deguelin is a naturally occurring rotenoid with strong cancer chemopreventive and antitumor activities. In the present study, we investigated the antitumor activity of deguelin against MPC-11 murine myeloma cells and the possible mechanism of action in vitro. Our results revealed that deguelin inhibited the proliferation of MPC-11 cells in a concentration- and time-dependent manner and caused the apoptotic death of MPC-11 cells. Following exposure to deguelin, the phosphorylation of Akt was decreased. The inhibition of cell growth may be associated with decreased levels of phosphorylated Akt. Deguelin-induced apoptosis was characterized by the upregulation of Bax, downregulation of Bcl-2 and activation of caspase-3. In conclusion, deguelin inhibits murine myeloma cell proliferation by inducing apoptosis via regulation of the Bax/Bcl-2 ratio and by inhibition of the activation of Akt. Its potential as an anticancer agent against multiple myeloma warrants further investigation.