Cancer in Down syndrome (DS) is characterized by a well known and marked excess of leukaemia whereas few cohort studies are available on solid tumours in this population. Objective: To study the cancer mortality of DS in California. Study group: 16,808 DS cases (contributing 129,076 person-years) among 210,155 persons having received annual evaluations from the California Department of Developmental Services over the period 1988-2002 were followed. Methods: Cancer mortality in DS was compared with the Californian general population using age-standardized mortality ratios (SMRs) computed for various cancer sites (ICD-9 codes 140-208). Results: An excess of overall cancer mortality (SMR 2.6, 95% CI 2.0-3.2) was found with overall SMR for neoplasms of the lymphatic and hematopoietic system at 10.3 (CI 7.5-13.9) [lymphomas: 3.7 (1.3-8.0), lymphoid leukemias: 27.6 (17.5-41.4), other specified leukemias: 51.1 (1.3-285.0) and unspecified leukemias: 25.4 (13.1-44.3)]. Liver [5.6 (1.8-13.1)] and testicular cancer [12.5 (1.5-45.1) were also more common in DS. No cancer deaths from lip, oral cavity, or pharynx were reported in DS. Other sites showed no significant differences. Excluding neoplasms of lymphatic and hematopoietic systems, the SMR for remaining cancers was 1.2 (0.8-1.7). Conclusion: Our findings do not support the hypothesis of a decreased risk of solid tumours in general in DS and confirm increased risk of testis and liver cancers. Further studies taking into account hormonal and genetic factors are needed to better understand the specific tumour profile in DS.