Besides its role in desensitization and internalization of receptors, β-arrestin2 facilitates G protein-independent signaling through its ability to scaffold various signaling molecules. β-arrestin2 is widely distributed in the central nervous system, and mediates signal transduction of brain circuit. The aim of the present study was to investigate the role of β-arrestin2 in reward behaviors induced by cocaine. We assessed the conditioned place preference (CPP) induced by low (10 mg/kg), moderate (20 mg/kg) and high (30 mg/kg) doses of cocaine in Arrb2(-/-) mice and Arrb2(+/+) controls. In the Arrb2(-/-) mice, moderate and high, but not low, dose of cocaine induced pronounced increases of CPP scores, which were higher than those in the Arrb2(+/+) mice. Moreover, cocaine-induced locomotor activity was significantly lower in Arrb2(-/-) mice than that of Arrb2(+/+) littermate controls. Taken together, our results suggest a potential role of β-arrestin2 in the cocaine-induced rewarding behaviors.