Background: HCC is a leading cause of cancer-related deaths worldwide. LEN is now a first-line treatment option for patients with uHCC, based on the REFLECT study in which LEN was established as noninferior to sorafenib (SOR) for overall survival (OS); LEN also demonstrated statistically significant and clinically meaningful improvements in progression-free survival, time-to-progression, and objective response rate vs SOR. The safety profile of LEN was consistent with its known side-effect profile. This postauthorization safety study aims to better characterize the safety of LEN, including hepatotoxicity, in real-life conditions in a Western population. Methods: This prospective, open-label, observational study (NCT04763408) will enroll patients with advanced or uHCC in routine clinical practice whom the treating physician has decided to treat with LEN (n = 500) or SOR (n = 500) according to the product labels. Enrollment is planned for 60 sites across Europe, Australia, USA, and Russia. The primary endpoint is the safety of LEN (hepatic-related toxicity and overall safety profile with regard to serious adverse events, grade ≥3 adverse events, and dose modifications and discontinuations due to adverse events). Secondary endpoints include treatment patterns (duration of treatment, incidence of dose interruptions and dose reductions, relative dose intensity, and subsequent treatments) and OS with LEN. Similar efficacy and safety data will be collected with SOR as an internal control for the population. Additionally, associations will be explored between patients’ baseline characteristics and treatment decisions as well as clinical and safety outcomes. Visits will be scheduled according to routine practice. Patients will be followed from initiation of treatment until the end of observation (whichever occurs first: withdrawal of consent, loss to follow-up, death, or end of the study [ie, 6 months after the last patient is enrolled]). Safety will be collected from initiation of LEN or SOR until the earlier of: 28 days after LEN/SOR discontinuation or the end of observation for patients who did not discontinue. Patients will be followed for survival and subsequent anticancer treatments until the end of observation, irrespective of length of treatment. Clinical trial information: NCT04763408.