Retinal neovascularization (RNV) is a devastating pathological feature of numerous ocular diseases and is a major cause of blindness. In this study, we examined the effect and potential mechanism of interleukin-26 (IL-26) in the pathogenesis of RNV in an oxygen-induced retinopathy (OIR) model. OIR model was induced by exposure of hypoxia (75% oxygen) to C57BL/6J mice from postnatal day 7 (P7) to P12 and then returned to room air. A significant up-regulation of IL-26 was detected in the retina at P17 after OIR, and the expression of IL-26 was observed to be localized mainly in the retinal endothelial cells (RECs). Furthermore, recombinant (r) IL-26 could effectively prevented RNV by reduction the areas of RNV, and IL-26 deficiency markedly increased RNV formation. In addition, the increased expressions of nuclear factor of activated T-cell (NFATc) 1 and vascular endothelial growth factor (VEGF) in the retina at P17 after OIR were increased in IL-26-/-mice, and were down-regulated following r1L-26 treatment. Collectively, these data suggested a possibility that IL-26 suppressed RNV via NFATc1-VEGF pathway. (C) 2018 Elsevier Inc. All rights reserved.