Hepatitis D virus (HDV) is the cause of an unusually severe form of liver disease with distinct histologic features (morula cell) that occurs throughout northern South America and certain other areas of the world. Clinical studies of HDV dLsease worldwide indicate that there is, in fact, a wide variation in pathogenesis, and the reasons for these differences are presently unknown. One possible explanation is that factors associated with the viral genotype are determinants of HDV pathogenesis. In this study, nucleic acid sequences were determined for three different northern South American HDV isolates which were obtained from individuals with severe disease or a family history of severe disease, in areas that are hyperendemic for this dise pattern. (HBV), which provides the coat protein for the HDV virion (1,2). Compared with infection with HBV alone, coinfection of HDV with HBV is associated with a higher rate of fulminant hepatitis in an acute infection; and superinfection with HDV ofindividuals with chronic HBV infection can lead to both acute and more progressive, chronic liver disease (3). The HDV genome is a 1.68-kb single-stranded circular RNA which is similar to the RNA genomes of unusual pathogens of higher plants (reviewed in ref. 4). HDV produces one known protein, the hepatitis D antigen (HDAg), which is encoded on the antigenomic strand (5) and has two forms (6) that differ in structure by 19 amino acids at the C terminus (5, 7). These two forms also differ functionally: the short form (HDAg-p24) is required for RNA replication (8); the long form (HDAg-p27) suppresses viral RNA replication (9, 10) and is required for packaging of the HDV genome with hepatitis B surface antigen (HBsAg) (11). HDAg-p27 arises via a specific RNA editing process that occurs during HDV replication (12) and that is dependent on a specific structure in the HDV RNA (13).Viral hepatitis due to HDV infection, type D hepatitis, is found worldwide, and the complete nucleic acid sequence has