OBJECTIVE: To clinically study the antiviral effects of lamivudine and entecavir on patients with early-to-mid stage Hepatitis B related acute on chronic liver failure (HBV-ACLF). METHODS; A prospective, randomized, open and parallel controlled clinical trial was designed to observe the antiviral effects of nucleoside analogues on patients with early-to-mid stage HBV-ACLF. Three groups were set for controlled study, i. e. basic treatment group, lamivudine plus basic treatment group and entecavir plus basic treatment group. RESULTS: One month after treatment, the improvement rates of lamivudine group and entecavir group were 58.85% and 59.15% respectively, significantly higher than that of basic treatment group which was 34.84% (Chi(2) = 9.8323, P = 0.043). By the end of six months, the cumulative survival rates of patients with the antiviral treatments, i.e., lamivudine, entecavir, were 65.8%, 60.1%, significantly higher than that (42%) without the antiviral treatment (P = 0.045, P = 0.04 respectively). The cumulative survival rate in patients with a MELD score < 30 was higher than that with a MELD score over 30 (Chi(2) = 3.920, P = 0.048). For the patients with pretreatment HBV DNA > or = 10(7), the cumulative survival rate in patients with entecavir treatments group was higher than that of patients in basic treatment group (Chi(2) = 5. 014 P= 0.025). According to the Ordinal Regression analysis, antiviral therapy by using either lamivudine or entecavia could significantly increase the improvement rate of patients with early-to-mid stage HBV-ACLF. But severe complications, including hepatorenal syndrome, electrolyte imbalance and hepatic encephalopathy, medical history of liver cirrhosis, and pretreatment HBV DNA > or = 10(7) had significant impacts on prognosis of this group patients. CONCLUSIONS: Antiviral therapy by using either lamivudine or entecavia could significantly increase the survival rate of patients with early-to-mid stage HBV-ACLF.