THE monoamine oxidase-B inhibitor L-deprenyl (Selegiline) is effective in treating Parkinson's disease and possibly Alzheimer's disease. The neuroprotective property of L-deprenyl may be unrelated to the inhibition of monoamine oxidase-B. Since nitric oxide (NO) modulates activities including cerebral blood flow and memory, we examined the effect of L-deprenyl on NO. L-Deprenyl induced rapid increases in NO production in brain tissue and cerebral vessels. Vasodilation was produced by endothelial NO-dependent as well as NO-independent mechanisms in cerebral vessels. The drug also protected the vascular endothelium from the toxic effects of amyloid-β peptide. These novel actions of selegiline may protect neurons from ischemic or oxidative damage and suggest new therapeutic applications for L-deprenyl in vascular and neurodegenerative diseases.