Abstract:  Plasma exchange has become an effective mode of blood purification in patients suffering from liver failure. To assist in patient recovery, we compared two plasma separators to identify a plasma separator with suitable pore sizes to remove toxic substances effectively, and retain important plasma components. The study focused on severe viral hepatitis patients. Of 206 rounds of plasma exchange, 137 were completed with the PS‐06 plasma separator (membrane pore size = 0.2 µm) and 69 with the EC‐4A plasma separator (membrane pore size = 0.03 µm). The efficacy of different plasma separators was compared using survival rate, changes in liver biochemistry, immunoglobulin, and complement parameters. The survival rate of patients treated with PS‐06 was 43.3% (13 of 30 patients). For patients treated with EC‐4A, two patients were bridged to liver transplantation successfully, and 57.9% (11 of 19 patients) survived. In both groups, the levels of total bilirubin, prothrombin time, and bile acid declined significantly. Compared to PS‐06, EC‐4A could retain significantly larger amounts of immunoglobulin and complements. Our study revealed that plasma exchange implementation with membrane pore size 0.03 µm could remove adequate bilirubin and bile acid, a class of toxins bound to plasma protein in severe viral hepatitis patients, and reduce the loss of essential plasma macromolecules.