HIF-1α induced by β-elemene protects human osteosarcoma cells from undergoing apoptosis. β-Elemene, isolated from more than 50 Chinese herbs and plants, has shown promising anticancer effects against a broad spectrum of tumors, such as lung, breast, prostate, cervical, colon and ovarian carcinomas (Wang et al. in Cell Mol Life Sci 62:881-893, 2005; Li et al. in Cell Mol Life Sci 62:894-904, 2005; J Pharm Pharmacol 62(8):1018-1027, 2010). But it has not reported in osteosarcoma cells. The aim of the present study is to investigate the antitumor effect of β-elemene on human osteosarcoma cancer cells and the molecular mechanism involved.β-Elemene inhibited the viability of human osteosarcoma cells in a dose-time-dependent manner. The suppression of cell viability was due to the induction of apoptosis. Our study also found that β-elemene treatment upregulated HIF-1α protein, which partially inhibits apoptosis. Knockdown of HIF-1α with small interfering RNA or co-treatment with the HIF-1α inhibitor YC-1 significantly enhanced the antitumor effects of β-elemene.Our study first found that β-elemene could increase the expression of HIF-1α through ROS and PI3K/Akt/mTor signaling pathway. And HIF-1α partially prevents human osteosarcoma cells from undergoing apoptosis. The anticancer effects of β-elemene was weakened by HIF-1α. So, we recognize that a combination of β-elemene with HIF-1α inhibitor might be a useful therapeutic option for osteosarcoma.