Individuals with Down syndrome have an increased risk of leukaemia, but reliable estimates of the age-specific risk of leukaemia are lacking and very little is known about the risk of solid tumours. We identified 2814 individuals with Down syndrome from the Danish Cytogenetic Register, and linked the data to the Danish Cancer Registry. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated on the basis of age- and sex-specific cancer rates in the general population. Sixty cases of cancer were observed, with 49.8 expected (SIR = 1.20; CI: 0.92-1.55). Leukaemia constituted 60% of the malignancies overall and 97% of the malignancies in children. The SIR for leukaemia varied considerably with age, being 56 (CI: 38-81) at age 0-4 years and 10 (CI: 4-20) at 5-29 years. No cases of leukaemia were observed after age 29. The cumulative risk of leukaemia by the age of 5 years was 2.1% and that by 30 years was 2.7%. Only 24 solid tumours were observed with 47.8 expected (SIR = 0.50; CI: 0.32-0.75). No cases of breast cancer were observed, with 7.3 expected (p = 0.0007). Increased risks of testicular cancer, ovarian cancer, and retinoblastoma were observed but were not statistically significant. The occurrence of cancer in Down syndrome is unique with a high risk of leukaemia in children and a decreased risk of solid tumours in all age groups. The distinctive pattern of malignancies may provide clues in the search for leukaemogenic genes and tumour suppressor genes on chromosome 21.