The proto-oncogene Akt is a potent inhibitor of apoptosis, and it is activated in many human cancers. A number of recent studies have highlighted the importance of the inositol 1,4,5-trisphosphate (IP3) receptor(IP3R) in mediating calcium (Ca2+) transfer from the endoplasmic reticulum (ER) to the mitochondriain several models of apoptosis. Akt is a serine-threonine kinase and recent data indicate the IP3R as a target of its phosphorylation activity. Here we show that HeLa cells, overexpressing the constitutively active myristoylated/palmitylatedAKT1 (m/p-AKT1), were found to have a reduced Ca2+ release from ER after stimulation with agonist coupled to the generation of IP3. In turn, this affected cytosolic and mitochondria Ca2+ response after Ca2+release from the ER induced either by agonist stimulation or by apoptotic stimuli releasing Ca2+ from intracellular stores. Most importantly, this alteration of ER Ca2+ content and release, reduces significantly cellular sensitivity to Ca2+ mediated proapoptotic stimulation. These results reveal a primary role of Akt in shaping intracellular Ca2+ homeostasis, that may underlie its protective role against some proapoptotic stimuli.