Studies on the natural history of chronic type B hepatitis have shown that loss of hepatitis B e antigen and seroconversion to antibody to hepatitis B e antigen are usually accompanied by remission of disease activity and improvement in serum aminotransferase levels. Twenty-five symptomatic patients with biopsy-documented chronic type B hepatitis were followed for 25 +/- 2 mo (mean +/- SEM) after disappearance of hepatitis B e antigen, hepatitis B virus-deoxyribonucleic acid, and deoxyribonucleic acid polymerase activity from the serum. Twenty-four patients developed the antibody to hepatitis B e antigen. All 25 patients demonstrated a decrease in serum aminotransferase levels, and most became asymptomatic. However, during subsequent follow-up, 8 of the 25 patients (32%) exhibited reactivation of chronic type B hepatitis manifested by abrupt elevation of serum aminotransferase levels and reappearance of serum hepatitis B virus-deoxyribonucleic acid, deoxyribonucleic acid polymerase activity, and, in 7 patients, hepatitis B e antigen. All 8 patients developed symptoms: 3 became icteric, 3 developed ascites, and 2 bled from esophageal varices. One of these patients died. Episodes of reactivation invariably occurred within 1 yr of loss of hepatitis B e antigen and lasted for up to 13 mo. These observations suggest that loss of hepatitis B e antigen and seroconversion to the antibody to hepatitis B e antigen do not necessarily imply permanent remission of chronic type B hepatitis, and subsequent spontaneous reactivation may be an important cause of progression of hepatic injury.