The system for assigning cause of death in animal studies of carcinogenicity at the National Center for Toxicological Research (NCTR) is described. An empirical study of the NCTR's experience with its current cause-of-death assignment system based on selected representative experiments is reported. Issues investigated include the degree of confidence associated with histologic cause-of-death assignment, potential age-, dose- and sex-related differences in assigned grades of certainty of cause of death, and frequencies of identification of various organ-specific and systemic diagnoses as the cause of death. Implications for age-adjusted statistical tests of carcinogenicity that require cause-of-death data are discussed.