Genetically heterogeneous animal models provide many advantages for research on aging but have been used infrequently. We present here lifespan and lesion data from a study of mice bred as a cross between (AKR/J x DBA/2J)F1 females and (C57BL/6J x SJL/J)F1 males. In such a four-way cross population, each mouse is genetically unique, but replicate populations of essentially similar genetic structure can be generated quickly, at low cost, and of arbitrary size from commercially available, genetically stable hybrid parents. We employed a protocol in which mice judged to be severely ill were euthanatized to obtain tissue in optimal condition for necropsy, and we were able to infer a likely cause of illness in 42 of 44 animals. Malignant lymphoma, including at least four histopathologically distinct subtypes, was the most common cause and was also a frequent incidental finding in mice dying of other causes. Neoplastic disease, benign or malignant, was the sole or a contributing cause of illness in 90% of the mice for which a cause could plausibly be assigned. A wide range of lethal and nonlethal degenerative lesions was also noted. The coefficient of variation for lifespan in these genetically heterogeneous mice was 26%, similar to that seen in analyses of recombinant inbred mouse lines. Baseline lifespan and pathology data on four-way cross mice is a useful prelude to the exploitation of this rodent model in tests of genetic and mechanistic hypotheses about aging.