Axonal degeneration is important during development but has not been thought to function in the intact mature nervous system. Here, we provide evidence that degeneration of adult axons occurs in the intact rodent brain through a p75 neurotrophin receptor (p75NTR)- and myelin-dependent mechanism. Specifically, we show that p75NTR-mediated axonal degeneration prevents septal cholinergic axons from aberrantly growing onto myelinated tracts in vivo or on a myelin substrate in culture. Myelin also triggers local degeneration of p75NTR-expressing sympathetic axons that is rescued by increasing TrkA signaling or elevating intracellular cyclic AMP. Myelin-mediated degeneration occurs when neurotrophins bind to p75NTR, and involves p75NTR-dependent sequestration of Rho guanine nucleotide dissociation inhibitor (Rho-GDI). Moreover, degeneration, but not growth inhibition, requires downstream activation of Rho and caspase-6. These data indicate that p75NTR maintains the specificity of neural connectivity by preventing inappropriate sprouting onto myelinated tracts and provide a physiological explanation for myelin inhibition after neural injury.