Despite a decline in cases of acute hepatitis B and the low hepatitis B virus (HBV) chronicity rates in adults, still some patients progress to HBV-related fulminant liver failure. In this review, we discuss treatment options that may prevent the progression of severe acute hepatitis B to fulminant liver failure and death. In severe acute HBV with prolonged prothrombin time and increased bilirubin, interferon failed to be effective while antiviral treatment, particularly with lamivudine, appears to improve survival (mean survival almost 80%). Outcome without antiviral therapy has remained considerably poor, whereas there is no convincing evidence of amelioration of HBV-targeted immunity. Of note, most patients who died or required transplantation despite lamivudine therapy, were started on lamivudine at advanced stages compared with those survived. This suggests that prompt and timely antiviral therapy is crucial. Owing to the abovementioned results the design of randomized placebo-control trials in the setting of severe acute hepatitis B seems unethical. On the contrary, the design of multicentre double-blind randomized trials to compare the efficacy between lamivudine and entecavir or even tenofovir in acute severe HBV cases is ideally needed, but these studies appear to be very difficult to perform considering that these cases are not frequent and therefore, it is almost impossible to have two arms adequately numerous and homogenous for statistical evaluation. Thus, in the absence of solid evidence based data, the hepatologists could treat their patients with severe acute hepatitis B with lamivudine or the most potent antivirals entecavir or tenofovir.