The aim of this study was to investigate the neuroprotective effects of a titolated extract from Rhodiola rosea L. (RrE) and of salidroside (Sa), one of the major biologically active compounds extracted from this medicinal plant, against oxidative stressor hydrogen peroxide (H2O2) and glutamate (GLU)-induced cell apoptosis in a human cortical cell line (HCN 1-A) maintained in culture. The results obtained indicate that exposure of differentiated HCN 1-A neurons to GLU or H2O2 resulted in concentration-dependent cell death. A 24 h pre-treatment with RrE significantly increased cell survival and significantly prevented the plasma membrane damage and the morphological disruption caused by GLU or H2O2, indicating that neurons treated with RrE were protected from the neurotoxicity induced by the oxidative stressor used. In addition, RrE significantly reduced H2O2 or GLU-induced elevation of intracellular free Ca2+ concentration. The results obtained have also shown that Sa caused similar effects in all experimental models used; however, the potency of the action was lower than that of the extract containing corresponding quantities of Sa. These findings indicate that RrE has a neuroprotective effect in cortical neurons and suggest that the antioxidant activity of the RrE, due to the structural features of the synergic active principles they contain, may be responsible for its ability to stabilize cellular Ca2+ homeostasis. Copyright © 2011 John Wiley & Sons, Ltd.