Hepatocellular carcinoma (HCC) is the most prevalent form of liver cancer, and ranks among the most lethal malignancies globally, primarily due to its high rates of recurrence and metastasis. Despite the urgency, no reliable biomarkers currently exist for predicting tumor recurrence in HCC. Telomerase reverse transcriptase (TERT) promoter mutations (TERTpm) and cellular tumor antigen p53 mutations (TP53m) have been frequently documented in HCC, but their combined clinical significance remains undefined. In this study, we investigated the clinical implications of TERTpm, TP53m, and their co-occurrence in 50 HCC tissue samples using the next-generation sequencing (NGS) technology. We identified TERTpm (C228T) and TP53m in 16 (32%) and 24 (48%) samples, respectively. Our findings indicate that these mutations are more prevalent in male patients (100% for TERTpm, 83.33% for TP53m), in those with solitary tumors (87.5% for both), in individuals with G2-G3 hepatitis (100% / 83.3%), and in cases of moderately differentiated tumors (75.0% / 83.3%). Furthermore, patients with both TERTpm and TP53m exhibited a significantly higher risk of tumor relapse (P < 0.05) and shorter progression-free survival (P < 0.05). Collectively, our results suggest that presence of both TERTpm and TP53m may serve as a robust predictor of tumor recurrence and a marker of poor prognosis in HCC.© 2025. The Author(s).