Simple SummaryThe treatment of hepatocellular carcinoma is burdened by an unacceptable recurrence rate after loco-regional treatment. Unlike all other solid tumors, no adjuvant or neoadjuvant systemic therapy schemes have been validated for hepatocellular carcinoma to date. Perioperative combination therapies could allow to optimize the radicality of treatments, reduce the recurrence rate and improve overall survival. Furthermore, systemic treatment could be used as bridging therapy in patients with hepatocellular carcinoma scheduled for liver transplantation with the aim of reducing the risk of dropout due to disease progression. The advent of immunotherapy in the therapeutic strategies of hepatocellular carcinoma could mark the start of a new era, revolutionizing the current management dogmas.AbstractDespite maximizing techniques and patient selection, liver resection and ablation for HCC are still associated with high rates of recurrence. To date, HCC is the only cancer with no proven adjuvant or neoadjuvant therapy used in association to potentially curative treatment. Perioperative combination treatments are urgently needed to reduce recurrence rates and improve overall survival. Immunotherapy has demonstrated encouraging results in the setting of adjuvant and neoadjuvant treatments for non-hepatic malignancies. Conclusive data are not yet available in the context of liver neoplasms. However, growing evidence suggests that immunotherapy, and in particular immune checkpoint inhibitors, could represent the cornerstone of an epochal change in the treatment of HCC, improving recurrence rates and overall survival through combination treatments. Furthermore, the identification of predictive biomarkers of treatment response could drive the management of HCC into the era of a precision medicine. The purpose of this review is to analyze the state of the art in the setting of adjuvant and neoadjuvant therapies for HCC in association with loco-regional treatments in patients not eligible for liver transplantation and to hypothesize future scenarios.