The formation of brain edema is the determining factor for survival of brain injury and stroke. Since high plasma levels of c-reactive protein (CRP) are associated with increased mortality, the aim of the present study was to examine the effects of HMG-CoA reductase inhibitors (statins) on CRP-induced blood brain barrier (BBB) disruption. Measurements of Trans-Endothelial-Electrical-Resistance (TEER) were conducted to monitor barrier integrity in a co-culture model (C6/ECV304) of the BBB. CRP (10–20 mg/ml) caused a significant decrease of TEER values (64.7 % of control; p<0.001, n=6) which was antagonized by cerivastatin and fluvastatin (0.01–0.25 mmol/l and 1–25 mmol/l, respectively). The barrier stabilizing effect of the statins was abrogated in the presence of the isoprenoid geranyl-geranyl-pyrophosphate (GGPP) but not by farnesyl-pyrophosphate (FPP). Inhibition of the nitric oxide (NO) synthase by L-NMMA (300 mmol/l) completely blocked the beneficial effects of cerivastatin and fluvastatin. Intracellular NO-levels were increased by the statins in a dose-dependent manner as observed using confocal DAF-fluorescence imaging. The barrier disrupting effects of CRP were also antagonized by the application of the NO donor SNP. In conclusion statins prevent CRP-induced BBB disruption by increasing intracellular NO levels, which requires the inhibition of GGPP dependent signaling mechanisms.