The relationship between hepatitis B virus deoxyribonucleic acid in serum and histologic activity was determined in 11 patients with corticosteroid-treated severe chronic active hepatitis B who underwent clearance of hepatitis B e antigen. All patients cleared hepatitis B virus deoxyribonucleic acid from the serum, and clearance preceded the loss of hepatitis B e antigen by 9-49 mo (mean 24 +/- 4 mo). Seropositivity for hepatitis B virus deoxyribonucleic acid was always associated with histologic features of chronic active hepatitis. Resolution of histologic activity followed the loss of hepatitis B virus deoxyribonucleic acid from the serum and it preceded clearance of hepatitis B e antigen in all patients. A transient elevation of serum aspartate aminotransferase activity occurred in 5 patients at the time that absence of hepatitis B virus deoxyribonucleic acid in serum was first demonstrated, and it was followed by resolution of histologic activity. The serum level of hepatitis B virus deoxyribonucleic acid slowly decreased or remained unchanged in all but 1 patient during long-term corticosteroid therapy. We conclude that hepatitis B virus deoxyribonucleic acid in serum is associated with histologic activity in corticosteroid-treated patients with severe chronic active hepatitis B. Disappearance of hepatitis B virus deoxyribonucleic acid from the serum precedes the loss of histologic activity and clearance of hepatitis B e antigen. Serum hepatitis B virus deoxyribonucleic acid levels usually do not increase during long-term corticosteroid therapy.