Proapoptotic BCL-2 family members BAX and BAK are required for the initiation of mitochondrial dysfunction during apoptosis and for maintaining the endoplasmic reticulum (ER) Ca²⁺ stores necessary for Ca²⁺-dependent cell death. Conversely, antiapoptotic BCL-2 has been shown to decrease Ca²⁺ concentration in the ER. We found that Bax^-/-Bak^-/- double-knockout (DKO) cells have reduced resting ER Ca²⁺ levels because of increased Ca²⁺ leak and an increase in the Ca²⁺-permeable, hyperphosphorylated state of the inositol trisphosphate receptor type 1 (IP3R-1). The ER Ca²⁺ defect of DKO cells is rescued by RNA interference reduction of IP3R-1, supporting the argument that this channel regulates the increased Ca²⁺ leak in these cells. BCL-2 and IP3R-1 physically interact at the ER, and their binding is increased in the absence of BAX and BAK. Moreover, knocking down BCL-2 decreases IP3R-1 phosphorylation and ER Ca²⁺ leak rate in the DKO cells. These findings support a model in which BCL-2 family members regulate IP3R-1 phosphorylation to control the rate of ER Ca²⁺ leak from intracellular stores.