Hepatitis B virus (HBV) infection is one of the leading causes of liver disorders such as liver cirrhosis and hepatocellular carcinoma. The prognosis of hepatitis B in patients with HIV co-infection is poor and chances of spontaneous clearance of HBV infection is less likely. To investigate if n-acetyl cysteine (NAC) would protect liver from toxic effects of efavirenz (EFVZ) as a possible combination therapy for hepatitis B. In vitro studies were performed using the HepG2 2.2.15 cell lines and duck model of hepatitis B (Guangxi Small Partridge; n=48), animals were randomly divided into eight groups (n=6 in each group). The drug groups were treated with three dosages of efavirenz (25, 50, 100 mg/kg/day) and three dosages of three dosages of efavirenz (25, 50, 100 mg/kg/day) plus N-acetyl cysteine (NAC) (20 mM). Both efavirenz and NAC inhibited the growth of HepG2.2.15 cells at high concentrations in a dosedependent manner. The treatment of HepG2.2.15 cells transfected with HBV, with efavirenz for 24 h also exhibited a dose dependent inhibitory effect on the secretion of HBsAg and HBeAg antigens. In duck HBV infection model, efavirenz plus NAC not only significantly reduced serum HBV DNA levels but also improved ALT and AST profile (p=0.03). Our study provides useful evidence that co-administration of NAC with efavirenz protects the toxic effect of efavirenz, in patients with hepatitis B infection.