The gray short-tailed opossum, Monodelphis domestica, is a newly established laboratory animal that is becoming increasingly important to biomedical research. Because little disease information is available for this species, we reviewed records for spontaneous gross and histologic lesions and microbiologic results in 150 M. domestica necropsies during an 11-year period. We identified 150 (91 female, 59 male) animals from 441 necropsy cases which were controls in experimental protocols or were members of the breeding colony. Initial statistical examinations indicated that the sample was representative of the living members of the breeding colony with respect to age, sex, and range of inbreeding. Causes of death and types of tumors were specifically evaluated. Females died earlier than males (22.6 +/- 13.0 months versus 30.9 +/- 11.9 months), but this difference was not associated readily with diet or inbreeding levels. The organ systems with the greatest lesion prevalences, in decreasing order, were the digestive, urogenital, cardiovascular, and respiratory systems. The most probable causes of all deaths were associated with the digestive system, followed by the cardiovascular and integumentary systems. The principal disease problems were rectal prolapse, congestive heart failure, and dermatitis. Neoplasia was found in 39 of the animals. The prevalence of neoplasia was greatest in the digestive system, followed by the endocrine, urogenital, integumentary, and hematopoietic systems. Pituitary adenoma was the most common neoplasm, followed by uterine leiomyoma and cutaneous lipoma. Specific microbially-induced diseases were not recognized, and endo- and ectoparasites were not found in colony-born M. domestica.