Objective To find the similarities and differences between SD rat and C57 mouse models of chronic renal failure established by 5/6 nephrectomy, and select an appropriate experimental animal for the study of the treatment and prevention of chronic renal failure. Methods 60 SD rats and C57 mice were randomly and equally divided into 5/6 nephrectomy group and sham operatied group. The mice and rats were killed at 4 weeks, 8 weeks and 12 weeks after the operation, respectively. Serum and renal tissue samples were collected for the detection and analysis of renal function and α-SMA. Results There was no significant difference in the survival rates between the rat and mouse models (P>0.05). The serum creatinine and urea nitrogen in the 5/6NX rat group showed a stable state at 8-12 weeks, which was different from that of the 5/6NX mouse group. Conclusions A 5/6 nephrectomy mouse model of chronic renal failure is successfully established. Although both 5/6 NX mouse and rat groups appear progressive renal failure after the operation, their disease processes are not quite the same. In clinic, appropriate experimental animals should be selected according to the length of the observation period in order to accurately show the disease states.