This study investigated mortality and causes of death between 1988 and 1999 in 14781 persons (6702 female) with Down syndrome in California, comparing age, sex, ethnicity, and other factors. Mean age at the start of follow-up was 14 years 8 months (SD 14y 10mo). During the study period 600 persons died. The standardized mortality ratio (SMR) for the population was 5.5. Blacks were at greater risk than whites, Hispanics, or Asians (relative risk = 1.5). Mortality declined during the period, especially for children with congenital heart defects. Leukemia (SMR = 17), respiratory illnesses (SMR = 27), congenital anomalies (SMR = 72), and circulatory diseases (SMR = 5.3) accounted for most of the excess mortality. With the exception of leukemia, cancer mortality was not different from that of the general population.