Introduction: The multiparametric nature of recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) still leads to uncertainty with its practical management. This study aims to characterize the main posttransplant recurrence patterns of HCC and to explore the therapeutic modalities targeting recurrence. Methods: Consecutive patients who underwent LT for HCC at a single tertiary center were analyzed. The time from first recurrence to death was investigated for each site of presentation. The impact of each recurrence-targeted treatment on survival was studied. Results: Of 660 patients with HCC, any recurrence occurred in 96 (15.4%) patients with a median time to recurrence of 20.0 months (95% CI: 15.6–23.8). Patients recurred across different patters including solitary distant locations (30.8%, n = 28), liver only (24.2%, n = 22), lung (18.7%, n = 17), multi-organ disease (17.6%, n = 16), and bone (8.8%, n = 8). Multi-organ and bone recurrences had the poorest survival, while solitary distant lesions and pulmonary recurrences had the best outcomes. Each treatment modality carried a distinctive survival. Conclusions: Patients recurred across 3 patterns with different prognostic implications. The benefit of each treatment option on distinct recurrence patterns appears to be influenced by the biological behavior inherent in the recurrence pattern itself.

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