Objective To explore the safety and efficacy of plasma diafiltration (PDF) in the treatment of liver failure. Methods Patients with liver failure requiring artificial liver treatment in West China Hospital of Sichuan University from December 2020 to December 2022 were selected and divided into three groups according to treatment modality: PDF group, double plasma molecular adsorption system (DPMAS) group and plasma exchange (PE) group. Serum albumin levels and total bilirubin (TB) levels were tested before and after treatments to compare the clearance of these substances among three groups. Adverse events were recorded. Results A total of 88 patients were included, with a total of 179 treatments conducted. Among them, 27 cases in PDF group were treated for 62 times. In PE group, 18 cases were treated for 33 times. In DPMAS group, 43 cases were treated for 84 times. There were no significant differences between the three groups in age, sex, TB, international standardized ratio, albumin, hemoglobin, blood pH value, blood sodium, blood potassium, blood free calcium, or lactate (P>0.05). There was no statistically significant difference in the absolute value of TB decrease, percentage of TB decrease, absolute value of albumin change, and percentage of albumin change before and after treatment among the three groups (P>0.05). Transient hypotension occurred in one patient in DPMAS group. There were two and three allergic reactions in PDF and PE groups, respectively. In addition, 2 patients in PE group had hypocalcemia. Conclusions PDF can be safely used in patients with liver failure, and its therapeutic effect on reducing bilirubin is similar to DPMAS and PE groups. Compared with PE, it needs less plasma supplement. As it can provide ultrafiltration, PDF would be helpful in patients with liver failure accompanied by renal insufficiency oliguria.