Objective To explore a multi-factor model that integrates enhanced CT parameters with the assessment of tissue rich in cysteinyl acidic secretory protein-like 1 （SPARCL1）， serum vascular endothelial growth factor （VEGF）， and thymidine kinase-1 （TK-1） for evaluating the clinical value and prognosis of primary liver cancer. Methods A total of 213 patients with primary liver cancer admitted to our hospital from January 2021 to August 2024 were selected as the study group. Meanwhile， 213 patients who underwent surgery or were hospitalized for benign liver diseases， including liver cirrhosis， liver hemangioma， and liver cysts， during the same period were selected as the control group. The enhanced CT parameters （arterial phase enhancement difference， venous phase enhancement difference）， SPARCL1 levels measured by fluorescence quantitative polymerase chain reaction， VEGF levels， and TK-1 levels measured by enzyme-linked immunosorbent assay were compared between the two groups. The diagnostic efficacy of each index alone and in combination for liver cancer was evaluated. All patients in the study group underwent transarterial chemoembolization （TACE） treatment. Post-operative follow-up was carried out for 1 year， and 4 cases had missing data. The patients were classified into groups according to their prognosis， with 156 cases in the good prognosis group and 53 cases in the poor prognosis group. A logistic regression model was used to analyze the prognostic factors， and the receiver operating characteristic （ROC） curve was plotted to evaluate the predictive value of each index for poor prognosis. Results The differences in venous phase enhancement between the study group and the poor-prognosis group， along with the SPARCL1 mRNA level， were lower than those in the control group and the good-prognosis group （P < 0.05）. Meanwhile， the difference in arterial phase enhancement， as well as the levels of VEGF and TK-1， were higher than those in the control group and the good-prognosis group （P < 0.05）. The AUC value of enhanced CT combined with the detection of SPARCL1， VEGF， and TK-1 for diagnosing primary liver cancer was higher than that of each indicator alone （P < 0.05）， with a sensitivity of 76.06% and a specificity of 81.22%. Logistic regression analysis confirmed that a low degree of differentiation （OR = 3.284， 95%CI： 1.886 - 5.718）， tumor stage Ⅲ-Ⅳ （OR = 2.793， 95%CI： 1.486 - 5.249）， lymph node metastasis （OR = 2.702， 95%CI： 1.224 - 5.965）， a large difference in arterial phase enhancement （OR = 2.702， 95%CI： 1.182 - 6.179）， a high VEGF level （OR = 2.423， 95%CI： 1.279 - 4.590）， and a high TK-1 level （OR = 2.344， 95%CI： 1.264 - 4.347） were all risk factors for the poor prognosis of primary liver cancer patients （all P < 0.05）. A large difference in venous phase enhancement （OR = 0.379， 95%CI： 0.189 - 0.762）， and a high SPARCL1 level （OR = 0.360， 95%CI： 0.151 - 0.858） were all protective factors for the poor prognosis of primary liver cancer patients （all P < 0.05）. Based on this， a risk factor model was constructed as follows： logit（P） = 0.867 + 1.189 × Degree of Differentiation + 1.027 × Tumor Stage + 0.994 × Lymph Node Metastasis + 0.994 × Difference in Arterial Enhancement - 0.969 × Difference in Venous Enhancement - 1.021 × SPARCL1 + 0.885 × VEGF + 0.852 × TK-1. The combined prediction probability for each patient was calculated according to this model. The ROC curve was plotted with this probability serving as the test variable. The results indicated that the AUC value of this combined prediction model was 0.905， with a sensitivity of 81.13% and a specificity of 82.69%. The predictive value of this model was relatively high. Conclusions The enhanced CT parameters， along with the serum levels of SPARCL1， VEGF， and TK-1， exhibit significant differences among patients with primary liver cancer and those with benign liver diseases， as well as among patients with different prognoses after TACE surgery. The combined detection of multiple indicators holds good diagnostic value for primary liver cancer. A low degree of differentiation， tumor stage Ⅱ-Ⅳ， lymph node metastasis， a large difference in arterial-phase enhancement， a high VEGF level， and a high TK-1 level are risk factors for the poor prognosis of primary liver cancer. In contrast， a large difference in venous-phase enhancement and a high SPARCL1 level are protective factors. The combined prediction model based on these indicators demonstrates good predictive efficacy for the short-term prognosis of patients and can offer a reference for clinical prognosis assessment.