Exercise training (EX) following percutaneous transluminal coronary angiography (PTCA) reduces progression to stenosis and increases event-free survival rates. Our aim was to determine if EX inhibits lesion development and/or alters the extracellular matrix (ECM) composition of the neointima (NI) in a porcine PTCA model. Miniature Yucatan swine were assigned to cage confinement (SED) or EX for 20 weeks. After 16 weeks all animals underwent a PTCA procedure of the LAD and LCX, with subsequent placement of an externalized jugular catheter. Animals recovered for 2 days and then resumed the previous protocol of SED or EX. Twelve days following PTCA, all animals received an intravenous BrdU injection to label proliferating cells. At 28 days following PTCA the animals were euthanized, the LAD and LCX excised, and underwent standard histological processing for total collagen, type I collagen, fibronectin, BrdU, and elastic fibers (VVG). Our results demonstrate that EX significantly decreased lesion size and NI proliferation (-48%) in the LAD (p<0.05), but not the LCX. Furthermore, EX attenuated type I collagen expression only in LAD, whereas total collagen was increased (5.9%) and fibronectin was decreased (-7.9%) in the NI of both vessels (p<0.05). In vitro assessment of type I collagen and fibronectin gene expression revealed attenuation in the up-regulation of these genes by the anti-inflammatory cytokines IL-6 and IL-10. In conclusion, EX following PTCA may increase event free survival rates following PTCA by decreasing lesion size and altering ECM composition, which are potentially mediated via IL-6 and IL-10.