Pentoxifylline (PTX) inhibits the effects of several cytokines and reduces injury-related collagen accumulation. The aim of the present study was to investigate the effect of PTX on the vascular response to injury. We treated rabbits with PTX (100 mg/kg/day) or placebo (saline) subcutaneously from 2 days before angioplasty of an iliac artery until euthanasia 7 or 28 days later. At 7 days after injury, PTX treatment was associated with a more differentiated (less proliferation, more smoothelin-positive) intimal smooth muscle cell phenotype. Furthermore, PTX reduced myofibroblast accumulation in adventitia. At 28 days after injury, PTX-treated rabbits had a 48.5% larger lumen area (P = 0.03) and a 28.1% larger area within the external elastic lamina (P = 0.04). There were no significant differences between PTX-treated rabbits and the placebo group with regard to neointima and media area. Angioplasty induced marked neoadventitial hyperplasia, which was reduced by 20.5% (P = 0.01) in the PTX-treated group. Finally, PTX reduced collagen density in all three arterial layers. We conclude that PTX treatment induces less proliferation within the vessel wall early after angioplasty and increases late lumen size after angioplasty by a positive effect on vascular remodeling.