Cardiomyocyte death (necrosis and apoptosis) plays a critical role in the progress of heart diseases. Salidroside, a phenylpropanoid glycoside isolated from Rhodiola rosea L, has shown cardioprotective effects in vivo. However, whether salidroside has a protective effect against cardiomyocyte death is poorly understood. The present study was aimed to investigate the cardioprotective role of salidroside and the underlying mechanisms in hypoxia-induced cardiomyocyte death. Cardiomyocytes pretreated with or without salidroside for 24 h were exposed to hypoxic condition for 6 h and then cell viability, necrosis, apoptosis, the expressions of HIF-1alpha and VEGF were investigated. Pretreatment with salidroside markedly attenuated hypoxia-induced cell viability loss, cell necrosis and apoptosis in a dose-dependent manner. Mechanistically, pretreatment with salidroside up-regulated the HIF-1alpha protein expression and induced its translocation. Moreover, the level of VEGF, a downstream target of HIF, was significantly increased in parallel with the level of HIF-1alpha following pretreatment with salidroside. However, 2-methoxyestradiol (2-ME2), a HIF-1alpha inhibitor, attenuated the protection of salidroside and blocked the increase of HIF-1alpha and VEGF. These data indicated that salidroside has protective effect against hypoxia-induced cardiomyocytes necrosis and apoptosis by increasing HIF-1alpha expression and subsequently up-regulating VEGF levels.