We found a strikingly low SMOR for all common tumors except leukemia and testicular cancer among Down syndrome-associated deaths. This low SMOR was present for all age groups and both sexes. Several explanations are possible for this finding, including triplication of tumor suppressor genes on chromosome 21, a decreased rate of cell division and consequently of cancer-causing mutations in trisomy 21 cells, and reduced exposure to carcinogens such as tobacco. A combination of factors seems likely, but further studies are needed to understand why people with Down syndrome die of cancer so infrequently.