Down's syndrome has been associated with organ-specific autoimmunity and 'premature aging'. We studied 27 individuals with Down's syndrome (all trisomy 21, no translocations aged 0.5 to 50 years). Subjects were not preselected for autoimmunity. Six subjects had a history of hypothyroidism and three additional subjects had anti-microsomal antibodies (euthyroid). Three subjects had insulin-dependent diabetes mellitus and one additional subject had islet cell autoantibodies (non-diabetic). The percentage Ia (Dr) positive T cells exceeded the normal range in 7/26 (27%). The percent CD4+ and CD8+ T cells were not significantly different from control. A subgroup of Down's syndrome subjects (less than age 10) had a premature increase in the percentage of 3G5+ (age-related) T cells. Normal individuals express a similar percentage of 3G5+ T cells at age 50 to 70 years. The presence of T-cell activation and 'premature T-cell aging' may predispose Down's syndrome subjects to organ-specific autoimmunity and age-related disorders.