Zinc finger motif‐1 (ZFM1) represses proinflammatory gene expression in vascular smooth muscle cells (SMCs) at a global level and thus may also be involved in the attenuation of growth factor‐induced phenotype changes in these cells. Using human primary cultured thymus vein SMCs, we have investigated the molecular mechanism by which a potent SMC mitogen, platelet‐derived growth factor‐BB (PDGF‐BB), causes a rapid decrease in ZFM1 expression in a concentration‐dependent manner and consequences thereof. Reporter gene analyses and chromatin immunoprecipitation showed that PDGF‐BB‐induced ZFM1 repression occurs at the level of transcription through replacement of the activating transcription factor Sp1 by Egr‐1. The subsequent drop in ZFM1 abundance disinhibits SMC proliferation, migration, and synthetic gene expression in a concerted manner. Stabilizing ZFM1 levels in a PDGF‐BB‐independent way with a GFP‐ZFM1 expression construct or by using Egr‐1‐specific decoy oligonucleotides abrogates all PDGF‐BB effects. Conversely, siRNA‐mediated knockdown of ZFM1 alone not only increases the sensitivity of SMCs for PDGF‐BB, but even mimics PDGF‐BB‐induced proliferation and gene expression. Our findings suggest that ZFM1 is an important factor for the stabilization of a contractile SMC phenotype under basal or mildly activating conditions and that, as a prerequisite for efficient action, PDGF‐BB must repress ZFM1 expression to alter the SMC phenotype.—Cattaruzza, M., Nogoy, N., Wojtowicz, A., Hecker, M. Zinc finger motif‐1 antagonizes PDGF‐BB‐induced growth and dediffer‐entiation of vascular smooth muscle cells. FASEB J. 26, 4864–4875 (2012). www.fasebj.org