Polymer coating can optimize the surface characteristics of metallic coronary stents and serve as a vehicle for local drug delivery. Major problems, however, include the lack of biocompatibility of the polymers used and the limited amount of drug that can be loaded onto the stent. Stainless-steel stents were spray-coated or spray-coated combined with a barrier coating using a fluorinated polymethacrylate PFM-P75 impregnated with different methylprednisolone concentrations. When spray-coated with highly concentrated methylprednisolone ( 33%) fluorinated polymethacrylate PFM-P75, the surface became progressively more rough. Adding a barrier coating, however, could decrease these surface irregularities of methylprednisolone-loaded PFM-P75 spray-coated stents. In vitro, most of the methylprednisolone was released in the first 48 hours. A barrier coating could dramatically slow down the drug release from 80% to 13% during the first 48 hours. Histomorphometric analysis showed that the inflammatory response and neointimal hyperplasia of methylprednisolone-loaded stents were lower than in control stents. Neointimal hyperplasia of methylprednisolone-loaded PFM-P75 stents spray-coated with a barrier coating was decreased compared to the non-barrier-coated methylprednisolone-loaded stents. In conclusion, spray coating enables the use of high methylprednisolone concentrations. A barrier coating could significantly slow down the methylprednisolone release. Methylprednisolone-loaded PFM-P75-coated stents could significantly inhibit the inflammatory response and neointimal hyperplasia. The response to methylprednisolone was related to the dose used and the release time of the drug.