OBJECTIVE CD4 T-cells secreting interleukin (IL)-17 are implicated in several human autoimmune diseases, but their role in type 1 diabetes has not been defined. To address the relevance of such cells, we examined IL-17 secretion in response to beta-cell autoantigens, IL-17A gene expression in islets, and the potential functional consequences of IL-17 release for beta-cells. RESEARCH DESIGN AND METHODS Peripheral blood CD4 T-cell responses to beta-cell autoantigens (proinsulin, insulinoma-associated protein, and GAD65 peptides) were measured by IL-17 enzyme-linked immunospot assay in patients with new-onset type 1 diabetes (n = 50). mRNA expression of IL-17A and IFNG pathway genes was studied by qRT-PCR using islets obtained from subjects who died 5 days and 10 years after diagnosis of disease, respectively, and from matched control subjects. IL-17 effects on the function of human islets, rat beta-cells, and the rat insulinoma cell line INS-1E were examined. RESULTS A total of 27 patients (54 ) showed IL-17 reactivity to one or more beta-cell peptides versus 3 of 30 (10 ) control subjects (P = 0.0001). In a single case examined close to diagnosis, islet expression of IL17A, RORC, and IL22 was detected. It is noteworthy that we show that IL-17 mediates significant and reproducible enhancement of IL-1beta/interferon (IFN)-gamma-induced and tumor necrosis factor (TNF)-alpha/IFN-gamma-induced apoptosis in human islets, rat beta-cells, and INS-1E cells, in association with significant upregulation of beta-cell IL17RA expression via activation of the transcription factors STAT1 and nuclear factor (NF)-kappaB. CONCLUSIONS Circulating IL-17(+) beta-cell-specific autoreactive CD4 T-cells are a feature of type 1 diabetes diagnosis. We disclose a novel pathway to beta-cell death involving IL-17 and STAT1 and NF-kappaB, rendering this cytokine a novel disease biomarker and potential therapeutic target.