The present study investigated the anti-proliferative and chemosensitizing effects of Crinum asiaticum var. japonicum against multi-drug resistant (MDR) cancer cells. The 80% methanol extract, chloroform ($CHCl_3$) fraction and butanol (BuOH) fraction of C. asiaticum inhibited the growth of mitoxantrone (MX) resistant HL-60 (HL-60/MX2) cells. When HL-60/MX2 cells were treated with the $CHCl_3$ and BuOH fractions, DNA ladder and sub-G1 hypodiploid cells were observed. Furthermore, the fractions reduced BcI-2 mRNA levels, whereas Bax mRNA levels were increased. These results suggest that the inhibitory effect of C. asiaticum on the growth of the HL-60/MX2 cells might arise from the induction of apoptosis. Treatment of HL-60/MX2 cells with the fractions markedly decreased the mRNA levels of the multi-drug resistance protein-1 and breast cancer resistance protein. The $CHCl_3$ fraction and hexane fraction increased MX accumulation in HL-60/MX2 cells. These results imply that the $CHCl_3$ fraction of C. asiaticum plays a pivotal role as a chemosensitizer. We suggest that components of C. asiaticum might have a therapeutic potential for the treatment of MDR leukemia.