Objective Three human hepatoma cell lines were injected into liver tissue of four mice with different immune function defects to establish orthotopic xenograft models of human hepatoma for comparison. Methods Human HepG2, HUH-7, and QGY-7703 cell suspensions were injected into the livers of mice with different immune function defects [BALB/ c nude, non-obese diabetic (NOD) SCID, NOG (NOD. Cg-PrkdcscidII2rgtm1Sug / JicCrl), and NPG mice]. Survival time, mortality, liver weight, B-mode ultrasound, and histology were used to analyze and compare the characteristics of liver cancer models in the various immunodeficient mice. Results B-ultrasonography and gross anatomical observations indicated that all experimental animals showed tumor nodule formation in liver tissue. Moreover, all animals injected with a HepG2 cell suspension into the liver died at about 20 days. The survival time of NOG and NPG mice was significantly shorter than that of BALB/ c and NOD SCID mice ( P <0. 001). Experimental groups with injected HUH-7 and QGY-7703 cell suspensions into the liver were autopsied at day 92 and 104, respectively. The liver volumes of NOG and NPG model mice were increased significantly and formed large tumor masses, whereas BALB/ c nude and NOD SCID mice showed only small tumor nodules in liver tissues. The weights of NOG and NPG mouse livers were significantly higher than those of BALB/ c nude and NOD SCID mouse livers ( P < 0. 05). Histological examination showed that all groups of animals exhibited tumor cell growth with large areas of necrosis and some animal lung tissues had tumor metastasis. Conclusions Compared with BALB/ c nude and NOD SCID mice, hepatoma cells grow more rapidly in the liver tissues of NOG and NPG mice, and the survival time is short, the liver volume is large, and the weight is increased.The human hepatoma cell lines can complete malignant proliferation in NOG and NPG mice in a short time for time-efficient model study. Therefore, human-derived hepatocyte xenografts in NOG and NPG mice are an ideal model for the development of anti-hepatoma drugs.