Vessel luminal narrowing after percutaneous coronary intervention (PCI) is characterised by platelet aggregation, release of growth factors, inflammatory cell infiltration, medial smooth muscle cell (SMC) proliferation, proteoglycan deposition and extracellular matrix remodelling. It is broadly accepted that the central mechanism at the basis of the whole pathophysiological process of restenosis is inflammation, triggered by vascular injury and activated through autocrine or paracrine mediators. Glucocorticosteroids exert beneficial effects on platelet function, on SMC proliferation and on collagen synthesis as well as inflammatory cell migration and activation, thus interfering with several steps of the cascade leading to neointima formation and subsequent late lumen loss. Initial experiences with systemic administration of glucocorticoids after PCI failed to confirm the expected benefits of this treatment, probably as a result of inadequate dosage and pharmacokinetic calculations. Recently a short-term, high-dose immunosuppressive treatment scheme with oral prednisone has demonstrated remarkable clinical and angiographic results when prednisone was given orally at a dose of 1 mg/kg for 10 days, 0.5 mg/kg for 20 days and 0.25 mg/kg for 15 days. This treatment has dramatically reduced the incidence of clinical vascular events at 1 year compared with controls (relative risk 0.34; 95% CI 0.12, 0.96; p = 0.006) and reduced the incidence of angiographic restenosis below 10% in different clinical and angiographic subsets. Secondary effects of a short course of glucocorticoids are generally minor, predictable and reversible: gastric pain, water and salt retention and worsened hypertension manifest in nearly 10% of patients. The addition of diuretics and acid suppressants before discharge, and the upgrading of antihypertensive medication thereafter, if needed, are useful preventive measures to control these temporary disorders. A routine blood cell count 4 weeks after PCI is advised in patients receiving thienopyridines (clopidogrel or ticlopidine) in addition to prednisone to rule out infrequent haematological dyscrasias. Emerging evidence supports this strategy as a convenient and well tolerated alternative to more expensive and complex revascularisation procedures such as drug eluting stent (DES) implantation or cardiac surgery, provided that the treatment is reserved for carefully selected candidates, i.e. after the exclusion of those with diabetes mellitus, a recent transmural myocardial infarction, or contraindications to the administration of a short-course of high-dose glucocorticosteroids. The recent concerns regarding the long-term safety of first-generation DES and the as yet undetermined duration of dual anti-platelet treatment, further supports the need for a simple pharmacological treatment that can be applied in a large percentage of patients currently treated with PCI. Multicentre randomised studies aimed at defining the efficacy and safety of oral prednisone treatment compared with metallic stents and DES are ongoing, and will become available in upcoming years.