Mechanobullous disease was diagnosed in a male Belgian foal that had sloughed hooves at 30 hours and at 6 and 12 days of age. Histologic and electron microscopic studies disclosed that lesions were the result of separation of the basal epithelial cell layer from the lamina densa of the basement membrane zone along the lamina lucida. Results of immunofluorescence on tissue specimens were negative for immunoglobulin deposition. The breeding history of the foal's dam indicated that the foal was produced from breeding of the mare to its full sibling stallion. This same mare had produced a female foal, sired by a different stallion, which also had sloughed hooves during the first 2 weeks of life and had similar histologic and electron microscopic changes. This newly recognized disease of horses most closely resembles junctional-type epidermolysis bullosa described in human beings.