Abstract: Objective To investigate whether there were differences in susceptibility to adriamycin（ADR） nephropathy in C57BL/6 substrains, and to provide theoretical data for the construction of adriamycin nephropathy model of C57BL/6 strains. Methods Twenty-four male C57BL/6J and 24 male C57BL/6N mice were randomly divided into model group（adriamycin 15 mg/kg, single injection through tail vein） and control group, 24 male BALB/c mice were also randomly divided into model group（adriamycin 10 mg/kg, single injection through tail vein） and control group. All control groups were injected with the same amount of normal saline through the tail vein. After 0, 2, 4 and 6 weeks of modeling, urine samples were collected for 24 hours to detect urine protein/creatinine ratio in each group. After 2 weeks and 6 weeks, the mice were harvested and the blood albumin, total cholesterol, urea and creatinine were detected, and renal pathology in each group was observed. Results There was no significant difference in urinary protein/creatinine ratio between C57BL/6J and C57BL/6N ADR groups and control groups（P＞0.05）. There was also no significant difference in renal function, albumin and total cholesterol levels between ADR and control groups for the two substrains at 2 weeks and 6 weeks（P＞0.05）. While in BALB/c mice, the urinary protein/creatinine ratio and blood albumin were significantly different from those in the control group at 2 weeks after modeling urinary protein/creatinine ratio: 24.00±1.35 vs 5.95±1.18, P＜0.01; blood albumin:（19.85±3.16） vs（27.32±2.07） g/L, t=3.43, P=0.02.In renal pathology, the glomerular, tubular and interstitial morphology of mice in C57BL/6J and C57BL/6N groups were basically normal, and there was no statistical difference in glomerular sclerosis index and tubule interstitial injury score at 2 weeks and 6 weeks with the control group（P＞0.05）. While in BALB/c mice, focal segmental sclerosis, mesangial matrix of the glomerulus and protein tubule pattern were observed at 2 weeks, and inflammatory cell infiltration was observed in renal tubulointerstitium, and the pathology of the ADR group was further aggravated at 6 weeks of modeling. Conclusion C57BL/6J and C57BL/6N mice are not susceptible to adriamycin nephrotoxicity when given 15 mg/kg doxorubicin in a single injection through tail vein.