Insulin resistance (IR) is associated with an increased risk of cardiovascular diseases. The obese Zucker Rat (ZR) is a model of IR that shows markedly increased insulin and triglyceride concentrations without major changes in glucose. In this study we evaluated the response of obese and lean ZR to carotid balloon injury and determined potential mechanisms and treatments. The neointima to media ratio of obese ZR was greater than that of lean ZR starting at 14 days after injury and persisted to at least day 30. An enhanced inflammatory response to balloon injury in the obese ZR was reflected by significantly higher ED 1 positive macrophage cells in the injured vessel wall compared to that in lean ZR at 3, 7 and 14 days after balloon injury. Inflammatory mediators 12-lipoxygenase (12-LO) and signal transducer and activator of transcription (STAT) 4 were studied in neointimal lesions. 12-LO RNA expression was increased beginning at day 7 and showed increases of 4.3 fold on day 14 and 7 fold on day 30 in obese ZR compared to lean animals. Staining of phosphorylated STAT 4 (PSTAT 4),the activated form of STAT 4, in lesions from obese ZR was also increased compared to that in leans. We tested the effects of a novel anti-inflammatory agent Lisofylline (LSF) in the obese ZR. LSF markedly reduced neointimal formation in the obese ZR. LSF also reduced monocyte/macrophage infiltration into the vessel wall and the activation of PSTAT 4. These studies suggest the presence of an exaggerated injury response in the insulin resistant obese ZR model and that inflammation plays a major role in mediating neointimal growth.