A critical step in the management of HCC is the prognosis estimation. It helps physicians to inform patients and relatives about the expected outcome and to indicate the most appropriate treatment option. The prognosis prediction of HCC is very variable and depends on several factors. The first variable to take into account is the tumor extent (number, size and extension). In that regard, small solitary tumors can be successfully treated in most cases and long-term survivals are possible. Contrarily, the presence of tumor within a vessel or outside the liver indicates an advanced stage and worse prognosis; at that point only palliative therapies are available. Second, as previously highlighted, most cases of HCC appear within an underlying chronic liver disease. Therefore, the degree of liver function reserve determines not only the treatment options, but also the outcome. Finally, it is mandatory to assess the presence of cancer-related symptoms since it indicates an advanced disease and limits the tolerance and success of several treatment approaches.