The clinical response of red foxes (Vulpes vulpes) to the mange mite, Sarcoptes scabiei, was characterized by infection of five, 4-mo-old red foxes with S. scabieioriginally isolated from a wild red fox. The infected foxes and three uninfected control foxes were monitored with weekly complete blood counts and biweekly serum chemistry profiles, hypersensitivity tests, and evaluation of skin biopsies. After 7 wk, the foxes were treated and held free of infection for 2 mo. Six foxes, three previously infected and three with no history of exposure, were then infected with the same isolate of S. scabiei and followed for another 7 wk; two additional previously infected foxes were held as treatment controls, and two foxes with no history of exposure as naive controls. All infected foxes developed significant immediate (Type I) hypersensitivity reactions to a S. scabiei mite extract within 2 wk of exposure and maintained this reaction as long as 4 mo after clearance of mites. Pronounced mast cell hyperplasia and infiltration with eosinophils were the earliest inflammatory cell responses noted in biopsy samples from infected foxes and were maintained throughout infection. Infected foxes also showed significant increases in white blood cell counts, due primarily to increases in numbers of circulating neutrophils and eosinophils. Clinical response, severity of disease, and relative numbers of mites per cm² of skin of previously infected foxes and foxes undergoing their first infection did not differ. These results show that red foxes develop strong immediate hypersensitivity reactions to S. scabieibut, under our experimental conditions, did not exhibit resistance to reinfection.