*Purpose: The interplay between acute cellular rejection (ACR), immunosuppression and hepatocellular carcinoma (HCC) recurrence in patients who underwent liver transplantation (LT) for HCC is still not well-understood. We hypothesized that episodes of ACR and lower HCC recurrence rates are both a manifestation of a “robust” immune system. We sought to evaluate the impact of severe ACR (sACR) episodes on the risk of HCC recurrence following LT in a large single-center cohort.

*Methods: Patients transplanted with HCC between January 1998 and December 2018 were retrospectively analyzed. Severe ACR was defined as any episode of biopsy-proven Banff ≥6. Kaplan Meier and Cox proportional hazard survival analyses were performed.

*Results: Six hundred and forty five patients were analyzed, 104 with sACR and 491 patients without. Patients with sACR were younger than those without sACR (mean 56 vs 59 years, p=0.007), otherwise both groups had comparable baseline, tumor and preoperative characteristics. Patients with sACR had a higher 5-year HCC recurrence-free survival than those who did not suffer from sACR, although not statistically significant (90% CI 84-97 vs 86% 82-89, p=0.31). In multivariable analysis, sACR was not associated with HCC recurrence, while total tumor number (HR 1.1 CI 1-1.2 p<=0.001), tumor size on explant (HR 1.4 CI 1.2-1.7, p=0.007) and pre-transplant NLR (HR 1.08 CI 1.01-1.15, p=0.024) were. Finally, sACR patients had more total ACR rejections (≥Banff 3) than the no-sACR group (mean 3.1+/-2.1 vs 0.7+/-1.1, p<0.001)

*Conclusions: These findings from a large single-center experience suggest that episodes of severe ACR following LT for HCC do not significantly influence recurrence free survival. This is in marked contrast to the findings of Lai et al who reported increased recurrence in the ACR treated group. The relationship between immunocompetence and the risk of HCC recurrence needs further study.

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