AbstractBackground and AimsHepatocellular carcinoma (HCC) recurrence is common in patients treated with liver resection (LR). In this study, we aimed to evaluate the incidence and preoperative predictors of non‐transplantable recurrence in patients with single HCC ≤5 cm treated with frontline LR.MethodsFrom the Italian Liver Cancer (ITA.LI.CA) database, 512 patients receiving frontline LR for single HCC ≤5 cm were retrieved. Incidence and predictors of recurrence beyond Milan criteria (MC) and up‐to‐seven criteria were compared between patients with HCC <4 and ≥4 cm.ResultsDuring a median follow‐up of 4.2 years, the overall recurrence rate was 55.9%. In the ≥4 cm group, a significantly higher proportion of patients recurred beyond MC at first recurrence (28.9% vs. 14.1%; p < 0.001) and overall (44.4% vs. 25.2%; p < 0.001). Similar results were found considering recurrence beyond up‐to‐seven criteria. Compared to those with larger tumours, patients with HCC <4 cm had a longer recurrence‐free survival and overall survival. HCC size ≥4 cm and high alpha‐fetoprotein (AFP) level at the time of LR were independent predictors of recurrence beyond MC (and up‐to‐seven criteria). In the subgroup of patients with available histologic information (n = 354), microvascular invasion and microsatellite lesions were identified as additional independent risk factors for non‐transplantable recurrence.ConclusionsDespite the high recurrence rate, LR for single HCC ≤5 cm offers excellent long‐term survival. Non‐transplantable recurrence is predicted by HCC size and AFP levels, among pre‐operatively available variables. High‐risk patients could be considered for frontline LT or listed for transplantation even before recurrence.