Because of the nucleotide sequence diversity of different isolates of hepatitis C virus, it has become important to clarify whether distinct genotypes of hepatitis C virus vary with respect to pathogenicity, infectivity, response to antiviral therapy and geographic clustering. We assessed nucleotide sequence variability in the 5′ noncoding region of hepatitis C virus, using restriction enzymes to analyze the distribution of hepatitis C virus genotypes, in 80 patients with chronic hepatitis C virus infection. Genotypes were correlated with demographic, clinical and histological features. Thirty-seven patients were infected with type 1, 10 had type 2 and 8 had type 3, and another 23 were infected with a new distinct hepatitis C virus type now classified as type 4. Two were infected with variants whose classification are uncertain. Types 1, 2 and 3 were found in patients from the United Kingdom, southern Europe, Asia, Africa and South America. Nineteen of 23 type 4 genotype isolates were from Middle Eastern patients, compared with 0 of 37 type 1 isolates (p < 0.001). Of 21 Middle Eastern patients, 19 (90.4) had type 4 hepatitis C virus (p = 0.001, odds ratio = 9). We found no significant difference between the mean ages or mean serum aminotransferase concentrations between the various types. Types 1,2,3 and 4 were found in patients with mild-to-moderate disease or severe disease. However, 21 of 29 (72.4) patients with type 1 who underwent liver biopsy had severe chronic hepatitis, cirrhosis or hepatocellular carcinoma histologically; 8 had mild or moderate chronic hepatitis without cirrhosis (p = 0.03, odds ratio = 2.6). Poor response to interferon-α was noted in patients with type 1 disease. Our data suggest significant geographic clustering of type 4 disease in the Middle East area. Although different hepatitis C virus genotypes can be encountered in both mild and severe disease, type 1 hepatitis C virus may have important clinical implications. The prognostic importance of these genotypes will require prolonged follow-up studies. (Hepatology 1994;19:13–18).