Analysis of delta hepatitis virus (HDV) genomic RNA, derived from Greek patients from an area where HDV infection is associated with low pathogenicity, is described. In all isolates sequenced, which included 18/18 HDV cDNA clones derived from 6 different patients, irrespective of pathogenicity, a base change (T-->C) was found in position 1014. No significant differences in editing efficiency were found between isolates from inactive and active forms of the disease, although L-antigen was present in low to undetectable levels in the serum of 5/6 patients. An additional mutation was identified at position 578 (A-->G), which reestablishes the canonical base pair G/C with the mutated 1014 when the genome adopts the "rod-like" conformation. This finding supports the presence of this genome conformation in vivo and the requirement for the Watson-Crick base pair 1014/578. A mutation, found at amino acid position 170 (serine-->asparagine), appears to segregate with patients with inactive disease.