【Abstract】 Objective To investigate changes in MRI intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) parameters and serum levels of alpha-fetoprotein (AFP)-L3 and sine oculis homobox homolog 1(SIX1) protein of patients with liver cancer, and to analyze their correlations with liver cancer patients' clinicopathological features and their values in the diagnosis of liver cancer. Methods A total of 80 patients with liver cancer were selected as the study group, and 80 healthy patients undergoing physical examinations at the same time were selected as the control group. The apparent diffusion coefficient (ADC), perfusion fraction, and serum AFP-L3 and SIX1 levels were compared between the two groups and between the patients with different clinicopathological features in the study group. The Spearman correlation analysis was used to explore the correlations of ADC, perfusion fraction, and serum AFP-L and SIX1 levels with clinicopathological features in liver cancer patients. The receiver operating characteristic (ROC) curve was used to analyze the value of ADC, perfusion fraction, and serum AFP-L3 and SIX1 levels in diagnosing liver cancer. Results The ADC was lower, and the perfusion fraction and serum AFP-L3 and SIX1 levels were higher in the study group than in the control group (all P<0.05). In the study group, the ADC was lower, and the perfusion fraction and serum AFP-L3 and SIX1 levels were higher in patients in a higher American Joint Committee on Cancer (AJCC) stage or with tumor metastasis than in those in a lower AJCC stage or without tumor metastasis; the ADC was lower, and the perfusion fraction and serum AFP-L3 and SIX1 levels were higher in patients with incomplete capsule than in those with intact capsule (all P<0.05). According to the results of Spearman correlation analysis, perfusion fraction and serum AFP-L3 and SIX1 levels were positively correlated with both AJCC stage and tumor metastasis and negatively correlated with capsule integrity, while the ADC was negatively correlated with both AJCC stage and tumor metastasis and positively correlated with capsule integrity (all P<0.05). The ROC curve analysis results showed that, in the diagnosis of liver cancer, the combination of ADC, perfusion fraction, and serum AFP-L3 and SIX1 levels had a larger area under the curve than the single index (all P<0.05). Conclusion ADC is decreased, perfusion fraction and serum AFP-L3 and SIX1 levels are increased in patients with liver cancer, the abovementioned indexes are closely correlated with the AJCC stage, tumor metastasis, and capsule integrity, and their combination has a certain value in the diagnosis of liver cancer.