The article reports the nucleotide sequence of the hepatitis C virus (HCV) genome, derived from overlapping cDNA clones. The 9379-nucleotide sequence contains a single large open reading frame encoding a polyprotein precursor of 3011 amino acids. While HCV shares little overall homology with other viruses, its 5' nucleotide sequence upstream of the large open reading frame is similar to that of pestiviruses. The polyprotein also shares significant sequence similarity with helicases from animal pestiviruses, plant potyviruses, and human flaviviruses, and contains motifs conserved among viral replicases and trypsin-like proteases. A basic domain at the N terminus of the polyprotein is likely the nucleocapsid protein, and the C terminus contains the conserved replicase domain. The hydrophobic profiles of HCV, pestiviruses, and flaviviruses are similar, suggesting a common protein structure despite limited sequence homology. The 5' RNA region of HCV is highly conserved among different isolates, indicating a regulatory role. Partial sequence data from various HCV isolates show significant diversity, suggesting the presence of distinct genotypes. The genetic organization and diversity of HCV indicate it is most related to pestiviruses, with potential implications for classification and understanding its relationship to flaviviruses.The article reports the nucleotide sequence of the hepatitis C virus (HCV) genome, derived from overlapping cDNA clones. The 9379-nucleotide sequence contains a single large open reading frame encoding a polyprotein precursor of 3011 amino acids. While HCV shares little overall homology with other viruses, its 5' nucleotide sequence upstream of the large open reading frame is similar to that of pestiviruses. The polyprotein also shares significant sequence similarity with helicases from animal pestiviruses, plant potyviruses, and human flaviviruses, and contains motifs conserved among viral replicases and trypsin-like proteases. A basic domain at the N terminus of the polyprotein is likely the nucleocapsid protein, and the C terminus contains the conserved replicase domain. The hydrophobic profiles of HCV, pestiviruses, and flaviviruses are similar, suggesting a common protein structure despite limited sequence homology. The 5' RNA region of HCV is highly conserved among different isolates, indicating a regulatory role. Partial sequence data from various HCV isolates show significant diversity, suggesting the presence of distinct genotypes. The genetic organization and diversity of HCV indicate it is most related to pestiviruses, with potential implications for classification and understanding its relationship to flaviviruses.