Autopsies reveal undiagnosed malignancies even in this era of modern diagnostic imaging and ancillary laboratory studies. The incidence of clinically undiagnosed malignancies related to primary cause of death in a university hospital setting has rarely been studied. Our objective was to determine the incidence of clinically undiagnosed fatal malignancies in an urban teaching hospital and to assess whether this incidence was influenced by the duration of hospital stay. We performed a retrospective analysis of consecutive adult hospital autopsies in which the primary cause of death was related to undiagnosed malignancy. The detailed autopsy report, clinical records, and relevant laboratory results from laboratory and hospital databases were reviewed. Eight hundred twenty-one adult autopsies were performed over 10 years. Sixty-nine clinically undiagnosed malignant neoplasms were found in 66 cases (8%). In 26 of these 66 cases, the undiagnosed malignant neoplasm was related to the primary cause of death (3.1%). The duration of hospital stay was less than 24 hours in 8 cases (30.7%), 2 to 7 days in 9 cases (34.6%), and greater than 7 days in 9 cases (34.6%). In 10 of these 26 cases (1.2%), there was suspicion of malignancy without definitive tissue diagnosis, and the average hospital stay was 4.9 days. In 16 (1.9%) of these 26 cases, malignancy was not clinically suspected, and the average hospital stay was 9.9 days. We conclude that despite the recent advances in diagnostic imaging and laboratory techniques, a subset of adult autopsies (3.1%) performed in an urban university hospital have clinically undiagnosed malignancy related to the primary cause of death. Malignancy was not clinically suspected in 1.9% of these cases. There is a need to conduct comprehensive "root cause" analysis in these cases for improvement of clinical care.