β-arrestins, a family of regulatory and scaffold proteins, are well-known negative regulators of G-protein-coupled receptors (GPCRS) including opioid receptors. Recent studies have shown that β-arrestin2 plays a potential role in inhibiting cell death. It has been reported that opioids such as morphine induce cell death at high concentrations (>500 μM for 24 hours), which is similar to morphine plasma concentrations in cancer patients receiving chronic morphine treatment for pain relievers. However, the role of β-arrestin2 in opioid-induced cell death remains to be elucidated. We report here that β-arrestin2 significantly blocks morphine-induced number of cell death in human breast cancer MCF-7 and MDA-MB231 cells. Suppression of endogenous β-arrestin2 by specific RNA interfering (RNAi) and morphine treatment significantly attenuates the levels of phosphorylated Akt compared with inhibition of β-arrestin2 or morphine treatment alone. However, blockade of morphine-induced cell death by β-arrestin2 seems to be dependent on the inhibition of caspase-8, as inhibition of β-arrestin2 and morphine treatment significantly enhanced the levels of cleaved caspase-8. These studies show for the first time that β-arrestin2 blocks morphine-induced cell death through anti-apoptotic Akt and pro-apoptotic caspase-8 pathways. Therefore, targeting β-arrestin2 may be useful for treating side effects of opioids as pain relievers for cancer patients.