Restenosis remains the major limitation of coronary angioplasty. The objective of this study was to develop microspheres able to be delivered at the angioplasty site for long-term drug release and to test their effects in a model of balloon angioplasty. Polylactic-co-glycolide acid microspheres (5-10 μm in diameter) were prepared by using an oil-in-water emulsion-solvent evaporation method. In vitro experiments with hydrocortisone-loaded microspheres revealed a hydrocortisone release for 4 weeks. We studied the in vivo effect of injection of microspheres into the arterial wall of New Zealand White rabbits by using a perforated balloon. Deep penetration of microspheres in the arterial wall was documented immediately after angioplasty. Intimal hyperplasia was assessed in iliac arteries 4 weeks after angioplasty. The morphometric analysis was performed in four groups of animals; the first group was subjected only to conventional angioplasty (control, n = 10), whereas the other three groups after conventional angioplasty were received perforated balloon angioplasty with saline (n = 10), microspheres (n = 10), or hydrocortisone-loaded microspheres (n = 7). Intramural injection of saline did not induce greater intimal hyperplasia compared with control (0.17 ± 0.03 vs. 0.18 ± 0.03 mm2, respectively). Microspheres injection was associated with a trend toward a greater degree of intimal hyperplasia that did not reach statistical significance. Hydrocortisone-loaded microspheres were associated with a significant reduction in intimal hyperplasia compared with unloaded microspheres (0.16 ± 0.02 vs. 0.26 ± 0.03 mm2, respectively). The polylactic-co-glycolide acid microspheres are well tolerated, easily injected into the arterial wall, and the increase of intimal hyperplasia is easily inhibited by release of hydrocortisone for 4 weeks after initial injury.