Hepatitis B virus-related acute-on-chronic liver failure (AoCLF) is associated with a high mortality rate. Plasma exchange (PE) is useful to bridge patients with AoCLF to liver transplantation or recovery. The aim of this study was to analyze the impact of the model for end-stage liver disease (MELD) score on 30-day survival in patients with AoCLF treated with PE or conventional medications and to evaluate the therapeutic effectiveness of PE. In this study, 62 enrolled patients with AoCLF who received PE treatment were compared with 131 patients treated with conventional medications. The MELD scores were calculated according to the original formula, and the 30-day survival in patients was recorded. The 30-day survival rate of the patients who received PE versus controls was 41.9% versus 25.2% (p < 0.05). The 30-day survival rate of patients in the PE group (50.0%) with a MELD score from 20 to 30 was higher than that of the control group (31.7%, p < 0.05); for MELD scores more than 30, there was no significant difference in two groups (8.3% vs. 0%, p > 0.05). PE seems to be efficacious and safe for the treatment of patients with AoCLF and significantly increased the survival rates of patients with a MELD score of 20–30.