Hepatitis B virus DNA (HBV DNA) in serum was measured by a Spot hybridization technique in a consecutive series of 79 cases with chronic HBV infection from Taiwan. HBV DNA was found in 96.3% (52/54) of HBeAg-positive, 66% (2/3) with neither HBeAg or anti-HBe and in 63.6% (14/22) of anti-HBe positive patients. The levels of HBV DNA in the HBe-Ag-positive patients were significantly higher than in the anti-HBe positive patients (median, 944 vs. 58 pg per ml, p less than 0.001). The mean ages increased from 28.7 years for the cases with high levels of HBV DNA, to 34.7 years for those with low levels (p less than 0.01) and to 41.0 years in those without HBV DNA in serum (p less than 0.05 when compared with those with low level of HBV DNA). Ninety per cent of patients (27/30) with high levels of HBV DNA showed only minor hepatic inflammatory activity, as did 91% (10/11) of those without HBV DNA. In contrast, histologic signs of chronic active hepatitis or chronic lobular hepatitis were demonstrated in 76% of cases (29/38) with low levels of HBV DNA. These data are consistent with the hypothesis that liver damage occurs during the period of clearance of hepatocytes supporting HBV replication, and are inconsistent with the view that HBV may be directly cytopathic. Thus, the natural history of chronic HBV infection may be divided into three phases.(ABSTRACT TRUNCATED AT 250 WORDS)