Axonal degeneration can be an important cause of permanent disability in neurological disorders in which inflammation is prominent, including multiple sclerosis and Guillain–Barré syndrome. The mechanisms responsible for the degeneration remain unclear, but it is likely that axons succumb to factors produced at the site of inflammation, such as nitric oxide (NO). We previously have shown that axons exposed to NO in vivo can undergo degeneration, especially if the axons are electrically active during NO exposure. The axons may degenerate because NO can inhibit mitochondrial respiration, leading to intraaxonal accumulation of Na+ and Ca2+ ions. Here, we show that axons can be protected from NO-mediated damage using low concentrations of Na+ channel blockers, or an inhibitor of Na+/Ca2+ exchange. Our findings suggest a new strategy for axonal protection in an inflammatory environment, which may be effective in preventing the accumulation of permanent disability in patients with neuroinflammatory disorders. Ann Neurol 2003