Aiming to remove the toxins produced during the course of severe hepatic failure, we combined hemodiafiltration and plasma exchange (patient plasma replaced by fresh frozen plasma in a twice-daily regimen) for treatment of five patients: two affected by primary nonfunction of a liver graft and three by fulminant hepatic failure. The simultaneous use of the two extracorporeal techniques allowed a rapid reduction in the administration of vasoactive drugs and a rapid, significant decrease in the indices of liver necrosis. Native liver functional recovery occurred in one case, and the wait for a second graft was made possible in the other four. Although it has been reported that the detoxifying efficacy of plasma exchange is optimal when the replaced volume of plasma is high, such a technique requires both long treatment times and high blood flows in the extracorporeal circuit, making it often hemodynamically intolerable. Our approach leads to replacement of smaller volumes, allowing lower blood flows that are better tolerated despite the often unstable hemodynamics of these patients. Liver transplantation and retransplantation remains the definite therapy for severe liver failure or primary nonfunction. However, the organ waiting time is unpredictable and often does not coincide with the patients' clinical needs. Thus alternative strategies must be developed until a suitable donor is found or there is spontaneous recovery. From this point of view, in our albeit limited experience, twice-daily plasma exchange combined with hemodiafiltration has proved to be an effective therapeutic approach.