The molecular mechanisms of hepatocellular carcinoma (HCC) are still not well understood. Gene microarray analysis showed that the expression of Intelectin-1 (ITLN-1) in tumor-adjacent normal liver tissue was 454.8 times higher than in the corresponding cancer tissue. ITLN-1 is a secreted soluble glycoprotein which has been reported to be associated with the occurrence and development of various tumor types. However, the prognostic significance of ITLN-1 in HCC remain unclear. Real-time fluorescence quantitative polymerase chain reaction was used to investigate 149 liver cancer cases for ITLN-1 mRNA expression. Immunohistochemistry and western blot analysis were used to ascertain protein expression of ITLN-1 in cancer and para-carcinomatous tissue, and further to evaluate the correlation between ITLN-1 mRNA expression and surgical prognosis after liver resection. The ITLN-1 mRNA and protein levels were significantly higher in adjacent normal liver tissues than HCC tissues. Real-time fluorescence quantitative polymerase chain reaction showed that the ITLN-1 expression was decreased in 78.5% (117/149) of HCC tissues compared with their corresponding adjacent liver tissues. Moreover, its low expression was significantly correlated with increased tumor size, tumor differentiation degree, degree of liver cirrhosis, capsule integrity, vascular invasion and tumor recurrence. Patients with high ITLN-1 expression had significantly better overall and recurrence-free survival after curative liver resection. Multivariate cox regression analysis showed that ITLN-1 was an independent predictor of surgical outcomes in HCC patients. The present study suggested that low ITLN-1 expression was associated with poor clinical outcome for HCC patients, indicating a novel biomarker for prognosis evaluation and a potential therapeutic target for HCC patients.Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.