Non-A, non-B hepatitis was recognized as a frequent consequence of blood transfusion for many years before the agent responsible, hepatitis C virus (HCV), was first cloned and sequenced in 1989 Very quickly it became apparent that viruses from different parts of the world were distinct, and after a frenzy of sequence analysis, a general picture has now emerged (1). Virus sequences can be divided into major types (identified by numbers) with nucleotide identities of <70% over complete genome sequences. Each type can be subdivided into subtypes (identified by letters) with identities of between 70 and 80%. Complete genome sequences are now available for all six HCV types and for several different subtypes of type 1 (a, b, and c), 2 (a, b, and c) and 3 (a, b, and "10a"). Very similar sequence relationships are obtained by analysis of subgenomic fragments, such as individual genes encoding structural or nonstructural proteins or a region as short as 222 nt of NS5B. On the basis of such comparisons, it is possible to differentiate consistently among six major genotypes (Fig. 1), and to an increasing number of subtypes (Fig. 2), now exceeding 10 for types 1, 2, 3, 4, and 6, but with only two known for type 5. Some isolates from southeast Asia have a controversial placement in this system, since they are less divergent from each other than virus types, but more divergent than subtypes However, phylogenetic and serological evidence suggests that they represent divergent subtypes of types 3 and 6 (2,3). Fig. 1. Phylogenetic tree of HCV NS5B sequences. Nucleotide sequences for positions 7975-8196 (numbered from the polyprotein AUG initiation codon) of NS5B were analyzed using the program Phylip as described previously (76). Major branches are labeled with the type number, and minor branches with letters indicating the subtype The variant "10a" can be considered as a subtype of type 3, and the variants "7a", "7b", "8a," and so forth, as subtypes of type 6 (2,3). Fig. 2. The discovery of HCV types and subtypes. The total number of HCV types (solid line) and subtypes (broken line) is indicated by year.