Osteopontin (OPN) is highly correlated with cyclosporine A (CsA) nephrotoxicity. As epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells plays an important role in CsA nephropathy, we investigated whether OPN mediated EMT of renal tubular epithelial cells upon CsA stimulation. OPN knockdown suppresses CsA induced EMT on NRK52E cells, and it also attenuates downregulation of E-cadherin and upregulation of α-smooth muscle actin (α-SMA) and fibronectin (FN) that are induced by CsA. OPN alone can induce EMT on NRK52E cells, which also results in upregulation of TGF-β1. Thus, OPN is a causative factor in mediating CsA induced EMT on NRK52E cells.