Prions are best known for their neurological toxicity when folded into a particular conformation. However, various functions have been ascribed to these prions when folded in their normal, nontoxic, cellular conformation called PrPC. PrPC is abundant in skeletal muscle, and its abundance increases in response to cellular stress; therefore, Stella et al. evaluated the effects of loss of PrPC (PrP-KO) on adult skeletal muscle regeneration in mice. Both wild-type and PrP-KO mice reconstituted with transgenic PrP served as controls. All three mouse strains showed similar morphological and fiber characteristics of the hind limb tibialis anterior (TA) muscle. However, regeneration after myotoxin injection, which causes necrotic death of the muscle but leaves the blood vessels, nerves, and satellite (muscle stem) cells intact, was delayed in the PrP-KO mice. At early times after injury (7 to 16 days), the regenerating PrP-KO mouse fibers were smaller, had fewer multinucleated fibers, and exhibited delayed expression (measured as protein abundance on Western blots) of the muscle differentiation marker neo-MHC. However, by 30 days all of the muscles had regenerated to the same extent. Macrophage recruitment is important for muscle regeneration, as is production of cytokines, such as tumor necrosis factor–α (TNF-α). Although macrophages were similarly abundant in all damaged muscles at all times after injury, the abundance of TNF-α was reduced 3 days after injury in the PrP-KO muscles. Regenerating PrP-KO muscles exhibited reduced activation of the stress-activated protein kinase p38 at early time points and reduced activity and abundance of the kinase Akt. Labeling of proliferating cells showed that the PrP-KO regeneration muscles had greater numbers of proliferating cells at early time points, which is consistent with the delayed appearance of the muscle differentiation marker neo-MHC and delayed reduction in the abundance of the stem cell marker Pax7. Thus, PrPC appears to play a role in the muscle response to injury and, although it is not required for regeneration, its presence speeds the rate of recovery.