Systemic treatment of hepatocellular carcinoma (HCC) has seen significant progress in recent years including the arrival of immunotherapy. While several large phase III trials have built the fundament for multi-line treatment, they have focused on a highly selected group of patients excluding potentially confounding comorbidities. As a result, high quality evidence for the systemic treatment of HCC patients with various comorbidities is missing. This review summarises the current knowledge on the use of currently approved medicines in patients with solid organ transplantation, human immunodeficiency virus, autoimmune disease, cardiovascular disease, diabetes, fibrolamellar HCC, mixed HCC-cholangiocarcinoma, decompensated cirrhosis (Child-Pugh B and C), patients of old age, with a significant bleeding history, on haemodialysis, and those with vascular invasion or portal vein thrombosis. The article highlights relevant knowledge gaps and current clinical challenges. To improve the safety and efficacy of HCC treatment in these subgroups, future trials should be designed to specifically include patients with comorbidities.