Statin treatment has been associated with a reduced risk of Alzheimer disease and decreased amyloid deposition in mouse models. No animal studies have reported effects of statins on tau aggregates and neurofibrillary tangles (NFTs), the pathological hallmarks of Alzheimer disease that correlate with dementia. We investigated the effect of statins on NFTs in a transgenic mouse tauopathy model and found the following: 1) 1-month treatment with the blood-brain barrier-permeable agent simvastatin in normocholesterolemic aged mice significantly reduced the NFT burden and decreased lectin-positive microglia; 2) simvastatin significantly decreased NFTs and improved T-maze performance in young animals treated for 8 months; 3) treatment of hypercholesterolemic mice for 5 months with blood-brain barrier-impermeable atorvastatin markedly reduced the NFT burden and decreased lectin-positive microglia; 4) nonstatin cholesterol-lowering strategies showed a modest NFT decrease compared with statin treatment; and 5) there was a positive correlation between microglial and NFT burden (r = 0.8). Together, these results suggest that statins reduce NFT burden irrespective of blood-brain barrier permeability at both early and late ages in long- and short-term treatment paradigms and under normocholesterolemic and hypercholesterolemic conditions. The decrease in microglia, coupled with the limited effect of nonstatin cholesterol lowering, suggests that the anti-NFT effect of statins may be related to their anti-inflammatory and not necessarily to their cholesterol-lowering properties. Statins may provide therapy against NFTs in tauopathies, particularly when NFTs are the major neuropathologic component.