Hemolytic Escherichia coli was isolated from the mammary glands of 8 ferrets with gangrenous mastitis. Clinical signs included firm swelling of one or more mammary glands and discoloration of the overlying skin. Peracute disease and acute septicemia were observed, and in some cases the animals rapidly became moribund. Antibiotic therapy alone did not alter the course of the disease. Wide surgical resection of the involved glands in combination with systemic antibiotic therapy (ampicillin 10 mg/kg, BID, and gentamicin 5 mg/kg, SID) was the most successful treatment. Histopathologic changes included extensive edema, hemorrhage, and necrosis, with a mixed leukocytic infiltrate and large numbers of bacteria. The agent of this disease was isolated from rectal swab specimens from clinically normal ferrets as well as ferrets that had mastitis.