Covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) is difficult to eradicate using current antiviral therapy. This study compares cccDNA reduction with relation to liver histology in nucleoside/nucleotide-naïve chronic hepatitis B patients receiving oral antiviral monotherapy (n = 35), including entecavir (ETV, n = 13), adefovir dipivoxil (ADV, n = 22) or placebo (n = 14). Serum HBV DNA, intrahepatic total HBV DNA and cccDNA are quantified. Histological hepatic examination is performed at baseline and at 48 weeks of treatment. Treatment with ETV or ADV shows significant median reduction in serum HBV DNA (−6.21 and −4.27 log10 copies/mL) and intrahepatic total HBV DNA (−1.69 and −1.23 log10 copies/cell). Intrahepatic cccDNA levels are reduced slightly in the ETV and the ADV groups, but do not differ statistically from the placebo group (−0.17 vs. −0.01 vs. 0.02 copies/cell). Only the level of intrahepatic cccDNA correlates with Knodell necroinflammation activity (r = 0.527, P < 0.001) and Ishak fibrosis severity (r = 0.348, P = 0.015) before treatment. Multivariate logistic regression analysis indicates that treatment-induced cccDNA reduction is associated with improved necroinflammation (P = 0.041) and fibrosis (P = 0.026). In conclusion, baseline intrahepatic cccDNA loads correlate with histologic activity. Although one-year ETV or ADV treatment is insufficient for cccDNA eradication, oral antiviral therapies may improve liver histology, probably by suppressing intrahepatic cccDNA. J. Med. Virol. 83:602–607, 2011. © 2011 Wiley-Liss, Inc.