Soluble interleukin 2 receptor (sIL-2R) levels reflect mononuclear cell activation and are elevated in a variety of autoimmune, neoplastic and infectious conditions. Several investigators have studied sIL-2R levels in patients with Type I diabetes mellitus (IDDM), but results have been conflicting. Our primary objective in this study was to compare sIL-2R levels of children and adolescents with newly diagnosed IDDM with those of age-matched controls. In addition, sIL-2R levels in a cohort of patients were followed longitudinally for 1 to 2 years after diagnosis. Serum sIL-2R levels of 38 IDDM children and adolescents (age < 20 years) were compared with levels of 39 nondiabetic, age-matched controls. Mean sIL-2R levels declined with age (P < 0.000005), and there was no significant difference in the regression line relating age and sIL-2R levels between patients and controls. The sIL-2R levels remained fairly consistent over 1-2 years of follow up. The presence of islet cell antibodies (ICA) had no apparent effect on sIL-2R levels in children with diabetes. The sIL-2R levels were similar in magnitude among first degree relatives of patients with IDDM compared to the range of unrelated subjects. It is our conclusion that sIL-2R levels are highest during infancy and decline throughout childhood. The sIL-2R levels do not appear to be clinically useful as a reflection of immune activation in patients with IDDM. Finally, there may be a genetic influence which partially regulates production of sIL-2R.