Recently, the protostrongylid nematode Parelaphostrongylus odocoilei has been reported in a new host species, thinhorn sheep (Ovis dalli). For the first time, we completed the life cycle of P. odocoilei in three Stone's sheep (O. dalli stonei) and two thinhorn hybrids (O. dalli stonei × O. dalli dalli), each infected with 200 third-stage larvae from slugs (Deroceras laeve). The prepatent period ranged from 68 days to 74 days, and shedding of first-stage larvae (L1) peaked at >10,000 L1 per gram of feces between 90 and 110 days postinfection. A total of 75, 27, and 14 adult P. odocoilei were recovered from skeletal muscles of three Stone's sheep. Starting in the prepatent period, all infected sheep lost weight and developed peripheral eosinophilia. At 2 wk before patency, two thinhorn hybrids developed neurologic signs (hind end ataxia, loss of conscious proprioception, and hyperesthesia) that resolved at patency. Eosinophilic pleocytosis and antibody to Parelaphostrongylus spp. were detected in the cerebrospinal fluid of the affected sheep, suggesting that the migration route of the “muscleworm” P. odocoilei may involve the central nervous system. Twenty days after treatment with ivermectin, neurologic signs recurred and larval shedding ceased in one infected thinhorn hybrid, whereas multiple treatments transiently suppressed but did not eliminate larval shedding in the other. During patency, two Stone's sheep with numerous eggs and larvae of P. odocoilei in the lungs died of respiratory failure following anesthesia or exertion. Parelaphostrongylus odocoilei has widespread geographic distribution, high prevalence, the possibility of causing neurologic and respiratory disease, resistance to treatment, and may constitute a significant emerging disease risk for thinhorn sheep.