In this study, we investigated whether an interleukin 2 (IL-2) secretion defect by peripheral blood mononuclear cells (PBMCs) after in vitro stimulation with phytohemagglutinin (PHA-M) occurs in either newly diagnosed or long-standing type I (insulin-dependent) diabetic patients and whether it is accompanied by a dysregulation of soluble IL-2— receptor (IL-2RS) production. PBMC cultures (2.5 × 10⁶ cells), unstimulated or stimulated with PHA-M (25 μg/ml), from 20 type I diabetic patients (10 with time since onset <3 mo and 10 with long-term diabetes of <3 yr) and 10 control subjects were studied for the production of IL-2 and IL-2RS in their respective supernatants. No difference was found in IL-2 production in unstimulated cultures of type I patients compared with control subjects, although a significant decrease from PHA-M-stimulated cultures was seen (newly diagnosed, 1.7 ± 0.3 ng/2.5 × 10⁶ cells; longstanding, 2.2 ± 0.3 ng/2.5 × 10⁶ cells; P < .001 and P < .05, respectively) compared with control subjects (3.6 ± 0.4 ng/2.5 × 10⁶ cells). In regard to the production of IL-2RS, no difference exists for unstimulated cultures, whereas, after PHA-M stimulation, both newly diagnosed and long-term-diabetic patients showed a decrease in the IL-2RS levels (318 ± 50 and 331 ± 62 U/2.5×10⁶ cells; P < .02 and P < .05, respectively) compared with normal subjects (463 ± 34.2 U/2.5×10⁶ cells). Thymus-activated cell phenotypes confirmed the T-lymphocyte activation after a 48-h culture period. The hypoproduction of IL-2 and IL-2RS in newly diagnosed patients may be the expression of the involvement of T-lymphocytes that have been activated continuously in vivo, but its presence in long-term patients suggests that the immunogenetic profile of the disease, involving immune-response genes also deputed to the control of lymphokine production levels, is such that type I diabetic patients are to be considered low IL-2 producers.