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Busulfan is the most commonly used drug for preconditioning during the transplantation of hematopoietic stem cells and male germ cells. Here, we describe side effects of high doses of busulfan in male mongrel dogs. Busulfan was intravenously administered to three groups of dogs at doses of 10, 15, and 17.5 mg/kg body weight. The total white blood cell, neutrophil, eosinophil, lymphocyte, monocyte, and platelet counts steadily reduced in a dose-dependent manner following busulfan treatment. The white blood cell, neutrophil, and monocyte counts recovered after 6 weeks of busulfan treatment, however, the eosinophil, lymphocyte, and platelet counts remained unaltered. Additionally, there was one fatality in the each of the groups that were administered 15 and 17.5 mg/kg busulfan. The gross lesions included severe hemorrhage in the stomach, intestinal tracts, mesentery and urinary bladder. Microscopic investigation revealed severe pulmonary edema and hemorrhage in the lungs, and severe multifocal to coalescing transmural hemorrhage in the intestines and urinary bladder. These results indicated that treatment with busulfan at doses higher than 15 mg/kg initiates severe bleeding in the internal organs and can have fatal results.