Intraocular inflammatory diseases are a common cause of severe visual impairment and blindness. In an acute mouse model of autoimmune retinal disease, we demonstrate that treatment with the HMG-CoA reductase inhibitor, lovastatin, suppresses clinical ocular pathology, retinal vascular leakage and leukocytic infiltration into the retina. Efficacy was reversed by co-administration of mevalonolactone, the downstream product of HMG-CoA reductase, but not by squalene which is distal to isoprenoid pyrophosphate metabolites within the cholesterol biosynthetic pathway. Lovastatin treatment over 7 days, which resulted in plasma lovastatin hydroxyacid concentrations of 0.098 ± 0.03μM, did not result in splenocyte production of Th2 cytokines but did cause a small reduction in antigen-induced T cell proliferation and a decrease in the production of IFN-γ and IL-10. Thus, contrary to expected outcome we demonstrate that it is possible to dissociate the therapeutic effect of statins from their activity on the Th1/Th2 balance. Statins inhibit isoprenoid pyrophosphate synthesis, precursors required for the prenylation and posttranslational activation of Rho GTPase, a key molecule in the endothelial ICAM-1 mediated pathway that facilitates lymphocyte migration. Consistent with inhibition of leukocyte infiltration in vivo, lovastatin treatment of retinal endothelial cell monolayers in vitro leads to inhibition of lymphocyte transmigration which may, in part, account for drug efficacy. Unlike lovastatin, atorvastatin treatment failed to attenuate retinal inflammatory disease despite showing significant clinical benefit in experimental autoimmune encephalomyelitis. These data highlight the potential differential activity of statins in different inflammatory conditions and their possible therapeutic use for the treatment of human posterior uveitis.