Myelomonocytic myeloproliferative disease in a horse was diagnosed on the basis of hematologic, enzymatic, and histopathologic findings. It was characterized clinically by depression, weight loss splenomegaly, lymphadenopathy, coagulopathy, and bacteremia. Hematologic findings included severe refractory anemia, thrombocytopenia, monocytosis, and pleomorphic leukocytes, with a left shift of the myeloid series. The serum lysozyme concentration was 14.5 microgram/ml (normal, less than 5 microgram/ml). The bone marrow contained many immature cells of the myeloid series and had a myeloid-to-erythroid ratio of 30.5 to 1. The horse died after brief hospitalization. Necropsy revealed generalized lymphadenopathy and hemorrhages throughout the body. Histopathologically, primitive cells were seen in several tissues. Cells that proliferated in the bone marrow were primarily myeloblastic, with some additional erythropoietic cells. Myeloblastic cells with evidence of normal erythropoiesis were seen in numerous lymph nodes and in the spleen, whereas primarily normal erythropoietic cells proliferated in the adrenal glands. Myeloid blast-type cells predominated in the lungs, myocardium, liver, and kidneys.