The observation that intracellular protein turnover rates participate directly in cell viability led to the development and clinical use of potent proteasome inhibitors. This study determined that the mechanism of apoptosis that is induced by inhibition of the proteasome of vascular smooth muscle cells (VSMC) was related to the intracellular accumulation of Bad, a BH3-only member of the Bcl-2 family of apoptosis regulators. Experiments confirmed that the apoptotic process was mitochondria- and caspase-dependent. Ubiquitination and accumulation of Bad in VSMC followed inhibition of the proteasome, and depletion of Bad using RNA interference prevented apoptosis that was induced by proteasome inhibition with PS-341. EGF receptor (EGFR) activation produced posttranslational modifications of Bad, providing the pro-survival signals that prevented apoptosis of smooth muscle cells during proteasome inhibition. Antagonists of the EGFR potentiated the apoptotic rate. In summary, the activities of the EGFR and the proteasome focused on Bad and the intrinsic apoptotic pathway and were involved integrally in determining viability of VSMC. These findings might prove useful in the management of diseases in which proliferation of vascular smooth muscle cells plays a central role. Copyright © 2007 by the American Society of Nephrology.