Background: Early recurrence of HCC after curative resection is common. However, the association between genetic alterations and early HCC recurrence, especially in Chinese patients (pts), remains largely unknown. Methods: We retrospectively analyzed 214 formalin-fixed paraffin-embedded (FFPE) tumor specimens of HCC patients that were collected from June 2016 to October 2021. Clinical outcomes related to frequently mutated genes were evaluated in 176 pts with a median follow-up time of 21.9 months. Tumor tissue samples were detected by OncoDrug-Seq 603-gene panel assay through next-generation sequencing. Early recurrence was defined as the appearance of an intra- or extrahepatic tumor nodule within 1 year of curative resection. Results: In multivariate analysis, three tumor suppressor genes related to early recurrence, namely PRDM1, NOTCH3, and MGA. PRDM1 mutations and NOTCH3 mutations were the risk factor for early recurrence (＜1 y after surgical resection) (hazard ratio (HR), 4.22; 95% confidence interval (CI), 1.96-9.06; p＜0.001 ) (HR, 2.96; 95% CI, 1.43-6.13; p=0.003). These two mutated genes were also significantly associated with overall survival (HR, 3.39; 95%CI, 1.23-9.34; p=0.018) (HR, 5.22; 95%CI, 2.10-12.99; p＜0.001). We found a trend toward an increased risk of early recurrence in pts with MGA mutation. (HR, 2.06; 95%CI, 1.05-4.05; p=0.027). Conclusions: Mutations in these three tumor suppressor genes were shown to be shorter time intervals to relapse after curative resection. We also demonstrated that pts who have these markers require more frequent monitoring and follow-up visits.