The mechanism by which misfolded proteins in the endoplasmic reticulum (ER) are retrotranslocated to the cytosol for proteasomal degradation is still poorly understood. Here, we show that importin beta, a well established nucleocytoplasmic transport protein, interacts with components of the retrotranslocation complex and promotes ER-associated degradation (ERAD). Knockdown of importin beta specifically inhibited the degradation of misfolded ERAD substrates but did not affect turnover of non-ERAD proteasome substrates. Genetic studies and in vitro reconstitution assays demonstrate that importin beta is critically required for ubiquitination of mutant beta 1-antitrypsin, a luminal ERAD substrate. Furthermore, we show that importin beta cooperates with Ran GTPase to promote ubiquitination and proteasomal degradation of mutant beta 1-antitrypsin. These results establish an unanticipated role for importin beta in ER protein quality control.