Objective Periodical imaging to monitor tumor growth in nude mice by pathology after establishment of an orthotopic liver cancer model to determine the appropriate treatment time. Methods HepG2 hepatoma cell line was injected into nude mice subcutaneously. The subcutaneous tumors were then cut into 1 mm³pieces and implanted into the livers of 15 nude mice. After model establishment, five nude mice in each group were examined by ultrasound (US) and magnetic resonance imaging (MRI), and the longitudinal diameter of the tumors was calculated at weeks 4, 6 and 8. Then, the nude mice were sacrificed and anatomized by an anesthetic overdose for observation of liver tumor formation,longitudinal diameter calculation, and pathological examination. Results An 80% tumor formation rate was observed in the nude mouse liver with uniform, focal, and solitary tumors. The detection rates of US and MRI were 75% and 100%respectively. The average longitudinal diameter of the tumors at 4, 6, and 8 weeks were 4, 7, and 11 mm, respectively.The Wilcoxon rank sum test revealed a significant difference between US and anatomical calculation ( P =0. 0059), and no significant difference between MRI and anatomical calculation ( P = 0. 208). At 4 and 6 weeks, the liver tumors in nude mice manifested with a homogeneous hypoecho in US, regular morphology and uniform strong signals with a clear boundary in T2WI, and compact atypical tumor cells with a large nucleus in pathological observation. At 8 weeks, the tumors presented with a heterogeneous echo in US, irregular shape and heterogeneous strong signals in T2WI, and obvious central necrosis in pathological observation. Conclusions Intrahepatic tissue implantation is effective for mouse model establishment of orthotopic hepatic carcinoma. The imaging features are correlated with the pathological findings. MRI is an effective imaging method to monitor the tumor growth throughout the entire course. Between 4 and 6 weeks after 1 mm³tumor tissue inoculation into the nude mouse liver may be the optimum period for initial tumor treatment.