N-methyl-d-aspartate (NMDA) subtype of glutamate receptors plays an important role during brain development and receptor activation has been shown to promote neuronal survival. The mechanisms by which NMDA increases neuronal survival are not fully understood. Here, we show that treatment with low concentrations of NMDA upregulates the neuroprotective molecule, X-chromosome-linked inhibitor of apoptosis protein (XIAP) in cultured hippocampal neurons at the post-transcriptional level. In contrast, NMDA treatment decreased mRNA and protein levels of caspase-3 in these neurons. The activation of the caspase-3 was also inhibited by NMDA, and the neurons were more resistant towards death caused by high concentrations of glutamate and staurosporine. Data on cytochrome c release in hippocampal neurons showed that NMDA pretreatment inhibits the mitochondrial pathway of cell death. The results demonstrate that the activation of NMDA receptors induces an anti-apoptotic program in hippocampal neurons that involves mitochondria and alterations of the levels of caspase-3 and XIAP. These findings are of importance for understanding the function of NMDA receptors in the control of neuronal survival during development and in other conditions.