Exogenous glucocorticoids inhibit neointimal proliferation in animals. We aimed to test the hypothesis that endogenous glucocorticoids influence neointimal proliferation; this may be mediated by effects on systemic risk factors or locally in vessels and modulated by either adrenal secretion or enzymes expressed in vessels that mediate local inactivation [11β-hydroxysteroid dehydrogenase type II (11β-HSD2) in endothelium] or regeneration [11β-hydroxysteroid dehydrogenase type I (11β-HSD1) in smooth muscle] of glucocorticoids. Femoral artery wire angioplasty was conducted in C57BL/6J, Apo-E(-/-), 11β-HSD1(-/-), Apo-E, 11β-HSD1(-/-) (double knockout), and 11β-HSD2(-/-) mice after glucocorticoid administration, adrenalectomy, glucocorticoid or mineralocorticoid receptor antagonism, or selective 11β-HSD1 inhibition. In C57BL/6J mice, neointimal proliferation was reduced by systemic or local glucocorticoid administration, unaffected by adrenalectomy, reduced by the mineralocorticoid receptor antagonist eplerenone, and increased by the glucocorticoid receptor antagonist RU38486. 11β-HSD2 deletion had no effect on neointimal proliferation, with or without eplerenone. 11β-HSD1 inhibition or deletion had no effect in chow-fed C57BL/6J mice but reduced neointimal proliferation in Apo-E(-/-) mice on Western diet. Reductions in neointimal size were accompanied by reduced macrophage and increased collagen content. We conclude that pharmacological administration of glucocorticoid receptor agonists or of mineralocorticoid receptor antagonists may be useful in reducing neointimal proliferation. Endogenous corticosteroids induce beneficial glucocorticoid receptor activation and adverse mineralocorticoid receptor activation. However, manipulation of glucocorticoid metabolism has beneficial effects only in mice with exaggerated systemic risk factors, suggesting effects mediated primarily in liver and adipose rather than intravascular glucocorticoid signaling. Reducing glucocorticoid action with 11β-HSD1 inhibitors that are being developed for type 2 diabetes appears not to risk enhanced neointimal proliferation.