Objective To investigate the difference between BALB/ c mutant curly mice and normal BALB/ c mice in the establishment of hepatocellular carcinoma models by two transplantation method. Methods Prepared H22 cells were subcutaneously injected ( 0. 2 mL/ mice) into the right lower extremity of BALB/ c mutant curly mice and normal BALB/ c mice, and subcutaneous tumors were removed 7 days later. Tumor tissue appeared at the injection site, suggesting that the model was successful. The better part of the edge texture of the tumor tissue was selected and cut into tissue micro- blocks (0. 5-1 mm in diameter), then transplanted into the liver in situ. Liver tumors were removed 15 days later. Tumor volume was calculated by measuring the length and diameter of subcutaneous and hepatic tumors with Vernier calipers, and the result of the two groups of mice were compared and analyzed. The two groups were stained with HE, and the morphological changes were observed by light microscopy. Results Tumors result ing from subcutaneous transplantation and original transplantation in curly mice were not only significantly larger than those in normal mice (P <0. 05), but also more uniform in size and three-dimensional in shape. Liver tumors in situ in curly mice were more closely related to the infiltration of normal liver tissue around them. Pathological result showed that there was no clear boundary between subcutaneous tumors and muscular tissues in curly mice, and the tumors were completely fused with each other. The in situ liver tumors in curly mice almost invaded the whole liver tissue in the field of vision. Conclusions The ability of BALB/ c mutant curly mice to form subcutaneous transplanted tumors and orthotopic transplanted tumors of liver cancer is significantly better than that of normal BALB/ c mice. This approach is expected to provide a high-quality animal model platform for the study of liver cancer.