Background: Treatment landscape in advanced/unresectable hepatocellular carcinoma (uHCC) has been rapidly changing. In June 2020, the first immuno-oncologic (I/O) + IV anti-angiogenic regimen for uHCC was approved as first line (1L) treatment in the US. As with any new therapy, it is key to understand the prevalence of medical conditions listed in patient medical history/comorbidities that could potentially influence physician choice of 1L therapy in uHCC patients. Methods: We conducted a retrospective chart review study using Cardinal Health's Oncology Provider Extended Network (OPEN). US medical oncologists identified newly diagnosed adult uHCC patients initiating 1L systemic therapy from June 2020 to April 2022. Based on the warnings and precautions section of the US FDA labels, medical conditions reported as part of patient medical history or comorbidities [including gastrointestinal (GI) bleeding risk, chronic kidney disease, autoimmune disorders, thromboembolic events] were identified from patient medical records. Less suitable was defined as the occurrence of ≥ 1 medical condition/comorbidity reported in the medical record. All patient data were deidentified. Proportions of patients with the above medical conditions or with physician-reported record of an esophagogastroduodenoscopy (EGD) procedure to assess risk of bleeding were calculated. Results: In the cohort of 433 uHCC patients initiating 1L systemic therapy, majority were male 287 (66%), Caucasian 244 (56%) with average age of 64 years. At 1L initiation, majority of the patients were 333 BCLC Stage C (77%) and 316 (73%) had ECOG performance status of 0 or 1. Approximately 160 (37%) were Child-Pugh B, 99 (23%) had non-alcoholic steatohepatitis (NASH), 176 (41%) had Hep-C etiology (among those tested), and 294 (68%) had liver cirrhosis. Prior to therapy initiation, 254 (59%) received EGD within 3 months. In the overall cohort, 221 (51%) patients were reported to have at least one condition listed as medical history/comorbidity that could make them less suitable to receive I/O + IV anti-angiogenic regimen. Upper/lower GI bleeding risk and chronic kidney disease were reported in 164 (38%) and 64 (15%) patients, respectively. History of thromboembolic events and autoimmune disorders were reported in 50 (12%) and 22 (5%) of patients, respectively. Conclusions: A significant proportion of the newly diagnosed uHCC patients were found to have at least one condition listed as medical history/comorbidity that would make them potentially less suitable for I/O + IV anti-angiogenic regimen. Our findings reinforce the importance of medical history and co-morbidity assessment in uHCC patients prior to therapy selection to optimize benefit-risk ratio for each patient.