We determined the sequence of the hepatitis delta virus (HDV) genome in 40 Japanese patients, most of whom were from the Miyako Islands, Okinawa, Japan. Consensus sequences from 33 HDV full genomes out of a total of 40 patients were determined by directly sequencing four partially overlapping PCR products. Phylogenetic tree analysis classified these 33 complete HDV genomes as HDV genotype I (two patients), genotype IIa (one patient) and genotype IIb (30 patients). Among the 30 genotype IIb patients, there were two clusters of genetic variants. One group consisted of six isolates showing significant homology with genotype IIb, previously reported from Taiwan. The other group consisted of 24 isolates, whose sequences formed a new genetic subgroup (genotype IIb-Miyako; IIb-M). When the genetic structures were compared in detail between IIb and IIb-M, characteristic variations were found in the C-terminal sequence of the large delta antigen-conferring packaging signal as well as the RNA editing site. Determination of subclasses of genotype IIb in a total of 37 patients, including seven HDV patients whose partial HDV sequence was determined, revealed eight patients with IIb and 29 patients with IIb-M. Although there was no significant difference in the clinical background or virological state of hepatitis B virus between these two groups, patients with genotype IIb-M showed greater progression of chronic hepatitis and cirrhosis than those with genotype IIb (P=0.0009). These data indicate the existence of a genetic subgroup of HDV genotype IIb, which is associated with different clinical characteristics and which could be related to genetic variations in functionally important parts of the HDV genome.