Type 1 diabetes (T1D) is a chronic disease characterized by an autoimmune-mediated destruction of insulin-producing pancreatic beta cells. Environmental factors such as viruses play an important role in the onset of T1D and interact with predisposing genes. Recent data suggest that viral infection of human islets leads to a decrease in insulin production rather than beta cell death, suggesting loss of beta cell identity. We undertook this study to examine whether viral infection could induce human b cell dedifferentiation. Using the functional human b cell line EndoC-bH1, we demonstrate that polyinosinic-polycytidylic acid (PolyI:C), a synthetic double-stranded RNA that mimics a byproduct of viral replication, induces a decrease in beta cell–specific gene expression. In parallel with this loss, the expression of progenitor-like genes such as SOX9 was activated following PolyI:C treatment or enteroviral infection. SOX9 was induced by the NF-kB pathway and also in a paracrine non–cell-autonomous fashion through the secretion of IFN-a. Lastly, we identified SOX9 targets in human b cells as potentially new markers of dedifferentiation in T1D. These findings reveal that inflammatory signaling has clear implications in human beta cell dedifferentiation.