Rationale Vascular smooth muscle cells (vSMCs) in mature animals normally reside in a quiescent state, expressing a distinct combination of contractile proteins, ion channels, and signaling molecules. However, in cases of vascular disease and injury, vSMCs are capable of being activated, shifting their phenotype through a continuum of cell fates. While the heparan sulfate proteoglycans syndecans, residing at cellular edges as transmembrane receptors, have emerged as powerful and complex regulators of cell function, their role in intercepting growth factors and therapeutic molecules modulating vSMC phenotype is unknown. Objective The purpose of this study was to examine the role of syndecan-1 in modulating the vSMC phenotype in the context of endogenous factors and drug treatments used for vascular disease. Methods and Results vSMCs were isolated from wild type (WT) and syndecan-1 knockout (S1KO) mice and cultured in different biochemical environments. Gene and protein expression studies indicated decreased α-smooth muscle actin (α-SMA) and calponin levels in S1KO cells relative to WT under simulated inflammatory conditions. Rapamycin treatment reversed the reduction in expression caused by S1KO, suggesting that the effects were, in part, mediated through mTORC1 signaling. In addition, S1KO vSMCs expressed higher levels of tissue factor, IL-6, and VCAM-1. These differences were maintained under treatment with heparin and TGF-β1, PDGF-BB, or atorvastatin. In-vivo studies with aortae from aged WT and S1KO mice indicated that S1KO arteries stained significantly lower for calponin. Conclusions Our findings not only provide insights into the fundamental cell surface receptors responsible for vSMC differentiation but also identify that the loss of syndecan-1 can make vSMCs more vulnerable to inflammatory molecular signals and potentially cause resistance to treatment with rapamycin and atorvastatin. Thus, preservation or enhancement of syndecan-1 expression may be a potential therapeutic target for altering the course of in-stent restenosis and atherosclerosis.