To assess the role of insulin receptor (IR) isoforms (IRA and IRB) in the proliferation of vascular smooth muscle cells (VSMCs) involved in the atherosclerotic process, we generated new VSMC lines bearing IR (wild-type VSMCs; IRLoxP(+/+) VSMCs), lacking IR (IR(-/-) VSMCs) or expressing IRA (IRA VSMCs) or IRB (IRB VSMCs). Insulin and different proatherogenic stimuli induced a significant increase of IRA expression in IRLoxP(+/+) VSMCs. Moreover, insulin, through ERK signaling, and the proatherogenic stimuli, through ERK and p38 signaling, induced a higher proliferation in IRA than IRB VSMCs. The latter effect might be due to IRA cells showing a higher expression of angiotensin II, endothelin 1, and thromboxane 2 receptors and basal association between IRA and these receptors. Furthermore, TNF-α induced in a ligand-dependent manner a higher association between IRA and TNF-α receptor 1 (TNF-R1). On the other hand, IRA overexpression might favor the atherogenic actions of IGF-II. Thereby, IGF-II or TNF-α induced IRA and IGF-I receptor (IGF-IR) overexpression as well as an increase of IRA/IGF-IR hybrid receptors in VSMCs. More importantly, we observed a significant increase of IRA, TNF-R1, and IGF-IR expression as well as higher association of IRA with TNF-R1 or IGF-IR in the aorta from ApoE(-/-) and BATIRKO mice, 2 models showing vascular damage. In addition, anti-TNF-α treatment prevented those effects in BATIRKO mice. Finally, our data suggest that the IRA isoform and its association with TNF-R1 or IGF-IR confers proliferative advantage to VSMCs, mainly in response to TNF-α or IGF-II, which might be of significance in the early atherosclerotic process.