B and T lymphocytes undergoing apoptosis in response to anti-immunoglobulin M antibodies and dexamethasone, respectively, were found to have increased amounts of messenger RNA for the inositol 1,4,5-trisphosphate receptor (IP₃R) and increased amounts of IP₃R protein. Immunohistochemical analysis revealed that the augmented receptor population was localized to the plasma membrane. Type 3 IP₃R (IP₃R3) was selectively increased during apoptosis, with no enhancement of type 1 IP₃R (IP₃R1). Expression of IP₃R3 antisense constructs in S49 T cells blocked dexamethasone-induced apoptosis, whereas IP₃R3 sense, IP₃R1 sense, or IP₃R1 antisense control constructs did not block cell death. Thus, the increases in IP₃R3 may be causally related to apoptosis.