Objective To explore the effects of Bixie Fenqing granules on proteinuria and podocyte podocalyxin and α-actinin-4 expression in renal tissues of rats with adriamycin-induced nephropathy. Methods Sixty specificpathogen-free SD rats were divided randomly into a blank group (n = 12) and model group (n = 48). A rat model of adriamycin-induced nephropathy was established by two injections of adriamycin into the tail vein. After successful establishment of the model, the rats were divided randomly into a model group, Bixie Fenqing granules group (6. 56 mL/kg) ( Chinese medicine group), prednisone group (6. 3 mL/ kg), and Bixie Fenqing granules + prednisone group (combination group). Treatments were administered once a day for 4 weeks and the blank and model groups were given the same amount of normal saline. Levels of 24 h urinary protein (24 h-UTP), serum total cholesterol (TC), and albumin were measured and pathomorphological changes in renal tissue were observed by hematoxylin and eosin and Masson staining. Expression levels of the podocyte-associated protein podocalyxin and α-actinin-4 in rat kidney tissues were detected by immunohistochemistry and Western blot. Results Serum TC and 24 h-UTP were significantly increased and albumin was significantly decreased in the model group compared with the blank group (P<0. 05). Renal tissues in model rats showed focal segmental scar formation, proliferation of mesangial cells and mesangial matrix, vacuolar degeneration of renal tubules and protein tubules in the lumen, and interstitial fibrous cell proliferation with inflammatory cell infiltration. Podocalyxin expression was significantly decreased and α-actinin-4 expression was increased (P<0. 05) in the model group compared with the control group. Conversely, compared with the model group, 24 h-UTP and serum TC were decreased and albumin was increased to different degrees in each treatment group (P<0. 05), glomerular and tubulointerstitial lesions were mild, with little renal interstitial edema and fibrosis, accompanied by a small amount of inflammatory cell infiltration, and podocalyxin expression was increased and α-actinin-4 expression was decreased (P<0. 05). Conclusions Bixie Fenqing granules can repair damaged podocytes via multiple targets, reduce UTP excretion, and protect the kidney by upregulating podocalyxin and down-regulating the expression of α-actinin-4.