Objective To examine whether cyclosporine A (CsA) treatment can induce anemia and changes in expression of erythropoietin (EPO) and its receptor (EPOR) in renal tissues of rats with chronic CsA nephrotoxicity. Methods Sprague-Dawley rats were treated daily with subcutaneous injection of vehicle (olive oil, 1 mL/kg, control group) or CsA (15 mg/kg, CsA nephrotoxicity model group) for 4 weeks. The renal function and hemoglobin (Hb) and hematocrit (Hct) levels were analyzed by Automatic Biochemistry Analyzer in the two groups. Masson Trichrome staining was used to examine the extent of tubulointerstitial fibrosis. Immunohistochemistry and Western blotting analysis were used to examine the expression of EPO and EPOR protein. And cell apoptosis was observed by TUNEL assay and electron microscope. Results Compared with the control group, CsA nephrotoxicity group showed renal insufficiency, tubulointerstitial fibrosis, and significantly more apoptotic cells (P<0.01). Meanwhile, CsA nephrotoxicity group also had anemia, manifested by significantly decreased Hb and Hct levels (P<0.01). Immunohistochemistry and Western blotting analysis showed that CsA treatment significantly decreased EPO expression and significantly increased EPOR expression compared with the control group (P<0.01). Furthermore, we also found that EPO protein expression was negatively associated with tubulointerstitial fibrosis (r=-0.729, P<0.001) and the number of TUNEL-positive cells (r=-0.841, P<0.001). Conclusion Renal EPO expression is decreased in rats with chronic CsA nephrotoxicity, which resulting in anemia; and tubular epithelial cell apoptosis induced by CsA is related to decrease of EPO protein.