HLA class I (HLA-I) molecules present intracellular antigenic peptides to CD8+ T lymphocytes during immune surveillance. In donors with type 1 diabetes, hyperexpression of HLA-I occurs in islets with residual insulin-producing β-cells as a hallmark of the disease. HLA-I hyperexpression is frequently detected beyond the islet boundary, forming a 'halo'. We hypothesized that this halo may reflect the diffusion of soluble forms of HLA-I (sHLA-I) from the islets to the surrounding pancreatic parenchyma. To verify this, we assessed the expression of total, cell surface and sHLA-I in β-cell lines and isolated human islets, following treatment with interferons (IFN)-α and IFN-γ. Consistent with the expression patterns of HLA-I in situ, both β-cell lines and cultured human islets dramatically upregulated total and surface HLA-I when exposed to IFNs. Concomitantly, sHLA-I release was significantly increased. HLA-I released within extracellular vesicles and cleaved forms of HLA-I did not significantly contribute to the sHLA-I pool. Rather, IFNs upregulated mRNA splice variants lacking the transmembrane domain. Our findings suggest that β-cells respond to IFNs by upregulating cellassociated and soluble forms of HLA-I. Soluble HLA-I may play a role in modulating islet inflammation during the autoimmune attack.