Aims/hypothesis. Interleukin (IL)-18 is a cytokine primarily produced by macrophages and capable of inducing T lymphocyte synthesis of interferon (IFN)-γ. An up-regulated synthesis of IFN-γ with consequential Type I cytokine dominance has been repeatedly shown in Type I (insulin-dependent) diabetes mellitus and thought to be involved in its pathogenesis. Because increased production of IFN-γ could be secondary to a dysregulated synthesis of IL-18, we compared the circulating levels of IL-18 in patients with newly diagnosed Type I diabetes with those of non-diabetic first-degree relatives and healthy control subjects. Methods. Serum samples were obtained from healthy control subjects, patients with newly diagnosed Type I diabetes, and their healthy first-degree relatives. The latter were subdivided into “low” and “high” risk prediabetics depending on whether they were negative or positive for two or more of the anti-pancreatic autoantibodies ICA, GAD, IA-2 and IAA. Serum levels of IL-18 were measured by solid-phase ELISA. Results. Interleukin (IL)-18 was above the detection limit of 25 pg/ml in 7 of 40 (17 %) healthy control subjects, in 5 of 35 (14 %) patients and in 3 of 30 (10 %) first-degree relatives at low risk of developing Type I diabetes. In contrast, IL-18 could be detected in 19 of 28 (68 %; p < 0.0001) relatives at high risk. The mean serum level of IL-18 was higher in these individuals when compared with the low-risk relatives, patients and control subjects. Conclusion/interpretation. IL-18 serum levels are increased selectively during the early, subclinical stage of Type I diabetes. [Diabetologia (2001) 44: 309–311]