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C57BL/6J (B6) mice are commonly affected by ulcerative dermatitis (UD), a disease of unknown etiology with poor response to treatment. To study the possible role of diet in UD, we compared skin changes in B6 female mice fed a high-fat diet with those of mice fed a control diet. In addition, skin samples from mice with no, mild, moderate, and severe clinical signs of UD were examined by light and transmission electron microscopy (TEM). Mice fed a high-fat diet for 2 mo had more skin mast cell degranulation than did mice fed the control diet for the same period. Regardless of diet, older mice had more skin mast cells and more of these cells were degranulating as compared with younger mice. Microscopic changes in very early lesions were characterized by an increase in dermal mast cells and degranulation with focal areas of epidermal hyperplasia with or without hyperkeratosis. As the condition progressed, a mixed but predominantly neutrophilic inflammatory cell infiltrate appeared in the dermis, with or without epidermal erosion and scab formation. TEM showed that dermal mast cell membranes had disrupted and released of large number of electron-dense granules, whereas degranulated mast cells were filled with isolated and coalescing empty spaces due to fusion of granule membranes. Ulceration appeared to occur very quickly, probably as result of intense scratching due to the pruritogenic properties of the histamine released from mast cell granules. This study showed a direct correlation between dietary fat and skin mast cell degranulation in female B6 mice. In addition, the number of skin mast cells and degranulation rates was higher in older mice. Treatments directed at preventing mast cell degranulation may result in better outcomes when applied early in UD cases. As noted previously in studies using caloric restriction, lower fat content in rodent diets may help prevent UD.