Background: Little is known about the mortality of individuals with Down syndrome who have lived at home with their families throughout their lives. The current study evaluates the predictors, causes and patterns of mortality among co-residing individuals in midlife with Down syndrome as compared with co-residing individuals with ID owing to other causes. Method: This paper examines mortality in 169 individuals with and 292 individuals without Down syndrome from 1988 to 2007. Dates and causes of death were obtained from maternal report, the Social Security Death Index and the National Death Index. Risk factors predicting mortality, including demographic variables, transition variables, and initial and change measures of health, functional abilities and behaviour problems, were obtained from maternal report. Results: Having Down syndrome is a risk factor of mortality, net of other risk factors including older age, poorer functional abilities, worsening behaviour problems, residential relocation and parental death. The causes of death among individuals with and without Down syndrome who are in midlife and co-residing with their families are similar, and are most commonly due to cardiovascular or respiratory problems. Conclusions: The findings indicate that midlife adults with Down syndrome who co-reside with their families generally exhibit similar causes of mortality as do midlife adults with intellectual disability owing to other causes, but show an elevated risk of mortality in midlife net of other variables, such as age and changes in functional abilities and behaviour problems.