BACKGROUND Fabry disease is an X-linked lysosomal deficiency of alpha-galactosidase A that results in cellular accumulation of galacto-conjugates such as globotriosylceramide, particularly in blood vessels. It is associated with early-onset stroke and kidney and heart failure. METHODS AND RESULTS Using [(15)O] H(2)O and PET, we found increased resting regional cerebral blood flow in Fabry disease without evidence of occlusive vasculopathy or cerebral hypoperfusion. Because nitric oxide is known to play an important role in vascular tone and reactivity, we studied plasma nitrate, nitrite, and low-molecular-weight S-nitrosothiol levels by chemiluminescence. Skin biopsy specimens and archived brain tissue were also examined immunohistochemically for nitrotyrosine. Plasma nitrate, nitrite, and low-molecular-weight S-nitrosothiol were in the normal range; however, enhanced nitrotyrosine staining was observed in dermal and cerebral blood vessels. After a double-blind, placebo-controlled trial of alpha-galactosidase A therapy, the resting regional cerebral blood flow in the treated group was significantly reduced, with a notable decrease of nitrotyrosine staining in dermal blood vessels. CONCLUSIONS These findings suggest a chronic alteration of the nitric oxide pathway in Fabry disease, with critical protein nitration that is reversible with enzyme replacement therapy.