Objectives Hepatocellular carcinoma (HCC) is difficult to diagnose early and progresses rapidly, making it one of the most deadly malignancies worldwide. This study aimed to evaluate whether salivary glycopattern changes combined with machine learning algorithms could help in the accurate diagnosis of HCC. Methods Firstly, we detected the alteration of salivary glycopatterns by lectin microarrays in 118 saliva samples. Subsequently, we constructed diagnostic models for hepatic cirrhosis (HC)

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... HCC using three machine learning algorithms: Least Absolute Shrinkage and Selector Operation, Support Vector Machine (SVM), and Random Forest (RF). Finally, the performance of the diagnostic models was assessed in an independent validation cohort of 85 saliva samples by a series of evaluation metrics, including area under the receiver operator curve (AUC), accuracy, specificity, and sensitivity. Results We identified alterations in the expression levels of salivary glycopatterns in patients with HC and HCC. The results revealed that the glycopatterns recognized by 22 lectins showed significant differences in the saliva of HC and HCC patients and healthy volunteers. In addition, after Boruta feature selection, the best predictive performance was obtained with the RF algorithm for the construction of models for HC and HCC. The AUCs of the RF-HC model and RF-HCC model in the validation cohort were 0.857 (95% confidence interval [CI]: 0.780–0.935) and 0.886 (95% CI: 0.814–0.957), respectively. Conclusions Detecting alterations in salivary protein glycopatterns with lectin microarrays combined with machine learning algorithms could be an effective strategy for diagnosing HCC in the future.