Objective To investigate the expression of C1q tumor necrosis factor-related protein 3 （C1QTNF3） in liver cancer tissue，its association with the clinicopathological features of patients，and its potential value in predicting the prognosis of liver cancer. Methods Related data were collected from TIMER，UALCAN，TNMplot，and GEO databases，and the bioinformatics methods were used to measure the expression level of C1QTNF3 in pan-cancer，normal tissue/liver cancer tissue，and cancerous tissue/paracancerous tissue. Cancerous and paracancerous tissue samples were collected from 90 patients with liver cancer，and related clinical data were collected，including age，sex，tumor diameter，and tumor number. The independent-samples t test or the paired t-test was used for comparison of continuous data between groups，and the chi-square test was used for comparison of categorical data between groups. The Kaplan-Meier method was used to plot survival curves，and the Log-rank test was used to investigate the association between the expression level of C1QTNF3 and the survival of patients with liver cancer. The Cox regression model was used to identify the risk factors for the prognosis of patients with liver cancer，and the receiver operating characteristic （ROC） curve was used to analyze the ability of C1QTNF3 expression at different time points for predicting the prognosis of patients with liver cancer. Results The bioinformatics analysis showed that the expression of C1QTNF3 was upregulated in various malignant tumors，especially in liver cancer tissue （P<0.001），and the expression level of C1QTNF3 in liver cancer tissue was significantly higher than that in normal tissue and paracancerous tissues （all P<0.01）. The immunohistochemical staining results of 90 patients with liver cancer showed that C1QTNF3 was mainly expressed in cytoplasm，with a small amount in nucleus，and it had negative expression in paracancerous tissue and positive expression in liver cancer tissue. The positive expression rate and strong positive expression rate of C1QTNF3 protein in liver cancer tissue were significantly higher than those in paracancerous tissue （positive expression rate： 76.67% vs 33.33%，χ²=34.141，P<0.01； strong positive expression rate： 54.44% vs 5.56%，χ²=51.217，P<0.01）. The liver cancer patients with a tumor diameter of ≥5 cm，an advanced stage，the presence of liver cirrhosis，negative HBsAg，and gamma-glutamyl transpeptidase （GGT）≥50 U/L had a significantly higher strong positive expression rate of C1QTNF3 protein than those with a tumor diameter of <5 cm，an early stage，the absence of liver cirrhosis，positive HBsAg，and GGT<50 U/L （all P<0.05）. The univariate Cox regression analysis showed that tumor diameter，recurrence，and C1QTNF3 expression were influencing factors for the prognosis of patients with liver cancer （all P<0.05），and the multivariate Cox regression analysis showed that the expression level of C1QTNF3 and recurrence were independent risk factors for the survival of patients with liver cancer （both P<0.05）. The survival curve analysis showed that for all patients with liver cancer，the patients with high （strong positive） expression of C1QTNF3 had significantly lower overall survival rate and disease-free survival rate than those with low expression （χ²=17.010 and 13.647，both P<0.001）； for liver cancer patients with a tumor diameter of ≥5 cm，an early/advanced stage，recurrence，the presence of liver cirrhosis，positive HBsAg，alanine aminotransferase （ALT） <40 U/L，ALT≥40 U/L，and GGT≥50 U/L，the patients with high expression of C1QTNF3 had a significant reduction in overall survival rate （χ²=11.086，5.578，5.295，19.159，16.391，13.774，10.119，8.152，and 12.035，all P<0.05）. The ROC curve analysis showed that C1QTNF3 expression had the strongest predictive potential at 5 years，with an area under the ROC curve of 0.77. Conclusion C1QTNF3 is highly expressed in liver cancer tissue，and the expression level of C1QTNF3 and recurrence are closely associated with the survival of patients with liver cancer. Patients with high expression of C1QTNF3 protein tend to have a lower survival rate.