Two types of clinical events, acute exacerbation and uneventful course, precede spontaneous HBeAg serocon-version to its antibody (anti-HBe) in chronic type B hepatitis. To examine the possible mechanism responsible for these two types of clinical events, serial serum specimens from 75 patients who underwent spontaneous HBeAg seroconversion were assayed for hepatitis B virus DNA by slot blot hybridization with 32P-labeled cloned hepatitis B virus DNA as probe. Of these 75 patients, 47 (62.7%) had episodes of acute exacerbation (ALT >300 IU per liter) within 3 months prior to HBeAg seroconversion. All of these 47 patients had high hepatitis B virus DNA levels (> 1,000 pg per ml) at the onset of acute exacerbation. Their serum hepatitis B virus DNA disappears shortly before or simultaneously with the HBeAg clearance in 27 patients (57.4%) and persisted but with decreasing levels for 2 to 40 months in 20 patients. Most of these patients had high α-feto-protein levels or evidence of bridging hepatic necrosis. In contrast, the serum hepatitis B virus DNA was undetectable for a minimum of 3 (3–17) months in the 28 patients who had an uneventful course before HBeAg seroconversion. Twenty of these 28 patients had well-documented episodes of acute exacerbation with high hepatitis B virus DNA levels, but with normal α-feto-protein and little evidence of extensive necrosis as far back as 6 to 27 months before HBeAg seroconversion. The data might suggest that all spontaneous HBeAg seroconversion in chronic type B hepatitis was preceded by acute exacerbation as a result of immune clearance of hepatitis B virus, and the clinical events occurred within 3 months before HBeAg seroconversion were related to the serum hepatitis B virus DNA levels.