NF-B-mediated inflammatory phenotypic switching of vascular smooth muscle cells (VSMCs) plays a central role in atherosclerosis and neointimal formation. However, little is known about the roles of circRNAs in the regulation of NF-B signaling. Here, we identify the involvement of circ-Sirt1 that was one of transcripts of SIRT1 host gene in VSMC inflammatory response and neointimal hyperplasia. First, in the cytoplasm, circ-Sirt1 directly interacts with and sequesters NF-B p65 from nuclear translocation induced by TNF- in a sequence-dependent manner. The inhibitory complex of circ-Sirt1-NF-B p65 is not dependent on IB. Second, circ-Sirt1 binds to miR-132/212 that interferes with SIRT1 mRNA, and facilitates the expression of host gene SIRT1. Increased SIRT1 results in deacetylation and inactivation of the nuclear NF-B p65. These findings illustrate that circ-Sirt1 is a novel non-coding RNA regulator of VSMC phenotype.