Acute tumor lysis syndrome (ATLS) is a potentially lethal condition precipitated by the massive release of intracellular components such as nucleic acids, potassium, and phosphorus, following a rapid and widespread lysis of tumor cells. Herein, the authors describe the high incidence and characteristic histopathologic lesions of acute ATLS in p53-deficient mice used in 2 short-term carcinogenicity studies. ATLS was a frequent cause of early death in p53^+/– mice in these studies and was consistently associated with the presence of disseminated lymphoma and leukemia. Although a heavy tumor burden and leukemia were present in all affected mice, the absence of ATLS in other mice with equally severe lymphoma and leukemia indicates that these tumor burdens are necessary but insufficient to cause ATLS in mice. The hallmark histopathologic findings of ATLS in mice are the disseminated microemboli composed of nuclear and cytoplasmic debris derived from lysed tumor cells. The mechanical obstruction of capillary beds by these microemboli appeared to be the proximate cause of the early deaths of mice in these studies. Microemboli may contribute to the pathogenesis of acute renal failure and other clinical signs associated with ATLS in other species. Recognition of ATLS in laboratory animals is critical in studies intended to evaluate the efficacy and/or toxicity of anticancer treatments, where early deaths due to ATLS might otherwise be attributed to test article toxicity. Further studies on the role of microemboli in the pathogenesis of ATLS may elucidate pathogenetic mechanisms and lead to improved approaches to clinical management and treatment of this potentially lethal condition.