Axons and their synapses distal to an injury undergo rapid Wallerian degeneration, but axons in the C57BL/Wld^S mouse are protected. The degenerative and protective mechanisms are unknown. We identified the protective gene, which encodes an N-terminal fragment of ubiquitination factor E4B (Ube4b) fused to nicotinamide mononucleotide adenylyltransferase (Nmnat), and showed that it confers a dose-dependent block of Wallerian degeneration. Transected distal axons survived for two weeks, and neuromuscular junctions were also protected. Surprisingly, the Wld protein was located predominantly in the nucleus, indicating an indirect protective mechanism. Nmnat enzyme activity, but not NAD⁺ content, was increased fourfold in Wld^S tissues. Thus, axon protection is likely to be mediated by altered ubiquitination or pyridine nucleotide metabolism.