Objective: Inflammation plays a major role in vascular disease. We have shown that leukocyte infiltration and inflammatory mediator expression contribute to vascular remodeling after endoluminal injury. This study tested whether increasing protein O-linked-N-acetylglucosamine (O-GlcNAc) levels with glucosamine (GlcN) and O-2-acetamido-2-deoxy-D-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc) inhibits acute inflammatory and neointimal responses to endoluminal arterial injury. Methods and Results: Ovariectomized rats were treated with a single injection of GlcN (0.3 mg g^-1, i.p.), PUGNAc (7 nmol g^-1, i.p.) or vehicle (V) 2 hrs prior to balloon injury of the right carotid artery. O-GlcNAc-modified protein levels decreased markedly in injured arteries of V treated rats at 30 min, 2 hrs and 24 hrs after injury but returned to control (contralateral uninjured) levels after 14 days. Both GlcN and PUGNAc increased O-GlcNAc modified protein levels in injured arteries compared to V controls at 30 min post injury; the GlcN-mediated increase persisted at 24 hrs but was not evident at 14 days. Proinflammatory mediator expression increased markedly after injury and was reduced significantly (30-50%) by GlcN and PUGNAc. GlcN and PUGNAc also inhibited infiltration of neutrophils and monocytes into injured arteries. Chronic (14 days) treatment with GlcN reduced neointima formation in injured arteries by 50% compared to V controls. Conclusions: Acute GlcN and PUGNAc treatment increases O-GlcNAc modified protein levels and inhibits acute inflammatory responses in balloon injured rat carotid arteries; 14 day GlcN treatment inhibits neointima formation in these vessels. Augmenting O-GlcNAc modification of proteins in the vasculature may represent a novel anti-inflammatory and vasoprotective mechanism.