Ninety-four patients, who were admitted with symptoms of liver disease and found to be positive for hepatitis B surface antigen and antibody to hepatitis B e antigen (anti-HBe), were examined for hepatitis B virus (HBV) DNA in serum and immunoglobulin antibody to hepatitis B core antigen and liver biopsies were stained for hepatic hepatitis B core antigen. Of 94 patients, 34 (36%) had evidence of HBV replication and 35 (37%) evidence of hepatitis D virus (HDV) superinfection. Most of the latter two groups of patients (greater than 70%) had evidence of chronic active hepatitis or active cirrhosis in their liver biopsies. The majority of these patients (greater than 80%) also had high levels of serum alanine aminotransferase (greater than 200 U/L) during the acute stage of their illness, and suffered from prolonged hepatic inflammation (greater than 1 year). Many of the patients (59%) also experienced frequent (1-6 episodes) relapsing exacerbations during a two-year follow-up period. Thus, persistent replication or reactivation of HBV and HDV superinfection were the two major causes of clinical exacerbations in anti-HBe-positive chronic HBV carriers in Taiwan, and also played an important role in the progression of their liver diseases and unfavorable outcomes.