Background: Percutaneous transluminal coronary angioplasty (PTCA) and stent implantation are associated with intimal hyperplasia and extracellular matrix (ECM) accumulation, resulting in restenosis. We showed that local delivery of 17-beta-estradiol (17βE) reduced restenosis following PTCA and stent implantation by 47 and 23%, respectively. Because estrogens decreased type I and type III collagen synthesis in vitro, we hypothesized that local delivery of 17βE may influence intimal hyperplasia formation by modulating ECM expression. Methods: Porcine coronary arteries underwent PTCA or stenting and were randomly assigned to 17βE or placebo. After 28 days, animals were sacrificed for histology and collagen type I and III content analysis. Results: Both collagen subtypes increased in the media by 1.7 to 2.6-fold after PTCA and by 15.7 to 16.1-fold after stenting, as compared to PTCA segments. In the neointima, the ratio of collagen type III to type I was 2.7 in stented arteries and only 0.3 in PTCA arteries. In the neointima of 17βE-treated animals, collagen type I (but not type III) content upregulation was limited by 53% after PTCA and by 74% after stenting. Conclusion: Local delivery of 17βE reduces restenosis, in part by decreasing the density of collagen type I in the neointima in PTCA and stented arteries.