Abstract β-Arrestin mediates desensitization and internalization of β-adrenergic receptors (βARs), but also acts as a scaffold protein in extracellular signal-regulated kinase (ERK) cascade. Thus, we have examined the role of β-arrestin2 in the βAR-mediated ERK signaling pathways. Isoproterenol stimulation equally activated cytoplasmic and nuclear ERK in COS-7 cells expressing β 1AR or β 2AR. However, the activity of nuclear ERK was enhanced by co-expression of β-arrestin2 in β 2AR—but not β 1AR-expressing cells. Pertussis toxin treatment and blockade of Gβγ action inhibited β-arrestin2-enhanced nuclear activation of ERK, suggesting that β-arrestin2 promotes nuclear ERK localization in a Gβγ dependent mechanism upon receptor stimulation. β 2AR containing the carboxyl terminal region of β 1AR lost the β-arrestin2-promoted nuclear translocation. As the carboxyl terminal region is important for β-arrestin binding, these results demonstrate that recruitment of β-arrestin2 to carboxyl terminal region of β 2AR is important for ERK localization to the nucleus.