Blood T-cells from 28 patients with type I (insulin-dependent) diabetes (IDDM) of variable duration were examined for the Tac antigen by immunofluorescence, and for proliferation in the presence of interleukin 2 (IL 2). The mean percentage of Tac+ cells in patients whose IDDM was of less than 2-yr duration was 6.2% compared with 2% in patients whose IDDM was of 3 or more years' duration, or in healthy controls. The percentage of Tac+ cells in the patients' blood correlated positively with the amount of thymidine uptake in a 24-h culture of blood mononuclear cells and with the percentage of T-cell blasts generated in a 6-day culture. The patients' T-cell blasts stained with OKT 4 or OKT 8, suggesting that each of these subsets is present in the activated T-cell population in the patients' blood. The T-cell blasts did not show specificity for pork insulin in an antigen restimulation assay. There was no correlation between increased Tac+ cells and the presence or absence of islet cell antibodies. If T-cell activation in IDDM occurs as a result of recognition of islet cell antigens, our results suggest that both HLA-DR-restricted (OKT 4+) and A-, B-, and C-restricted (OKT 8+) T-cell subsets contribute.