Background: The misfolding and aggregation of specific proteins has emerged as a key feature of several neurodegenerative diseases. In prion diseases, progressive disease and neuronal loss are associated with the accumulation of PrPSc, the misfolded isoform of PrPC. Previous in vitro studies suggest that cholesterol-lowering drugs inhibit the conversion of PrPC to PrPSc and the accumulation of the latter, possibly through the disturbance of cholesterol-rich membrane domains (lipid rafts). Objective: To examine the effect of simvastatin, a cholesterol-lowering drug, on prion disease progression and survival. Design: Controlled animal study. Setting: University medical center research laboratory. Subjects: Female mice from the FVB/N strain. Interventions: Peripheral and central nervous system inoculations with scrapie Rocky Mountain Laboratory inoculum. Main Outcome Measures: Clinical, immunological, pathological, and molecular assays were performed. Results: Simvastatin delayed disease progression, leading to increased survival in peripheral as well as central nervous system inoculations. Simvastatin's beneficial effect is mediated through the L-mevalonate pathway; however, it is independent of brain cholesterol levels. Interestingly, simvastatin treatment induced PrPSc accumulation in parallel with an induced neuroprotective effect. In accordance, we found that simvastatin induced immunomodulatory mechanisms in the brains of infected mice, affecting expression levels of specific microglial chemokines and cytokines. Conclusions: Simvastatin delays prion disease progression and increases survival in vivo, independently of the pathogenic conversion of PrPC to PrP Sc. We show that simvastatin's effects on neuroprotection are correlated with downregulation of Cox2 levels and induction of microglial activation in prion-infected mouse brains.