A prospective study was performed to establish whether infection with specific hepatitis C virus (HCV) genotypes was associated with an increased risk of development of hepatocellular carcinoma (HCC) in cirrhosis. A cohort of 163 consecutive hepatitis C virus antibody (anti-HCV)-positive cirrhotic patients was prospectively evaluated for the development of HCC at 6-month intervals by ultrasound (US) scan and alpha-fetoprotein (AFP) concentration. HCV genotypes were determined according to Okamoto. Risk factors associated with cancer development were analyzed by univariate and multivariate statistics. At enrollment, 101 patients (62%) were infected with type 1b, 48 (29.5%) were infected with type 2a/c, 2 (1.2%) were infected with type 3a, 1 (0.6%) was infected with type 1a, 3 (1.8%) had a mixed-type infection, and, in 8 patients (4.9%), genotype could not be assigned. After a 5- to 7-year follow-up (median, 68 months), HCC developed in 22 of the patients, 19 infected with type 1b and 3 with type 2a/c (P < .005). Moreover, HCC developed more frequently in males (P < .01), patients with excessive alcohol intake (P < .01), those over 60 years of age (P < .02), and in patients who did not receive interferon treatment (P < .02). Multivariate analysis showed that type 1b was the most important risk factor associated with tumor development (odds ratio 6.14, 1.77-21.37 95% confidence interval). Other independent risk factors were older age and male sex. Cirrhotic patients infected with HCV type 1b carry a significantly higher risk of developing HCC than patients infected by other HCV types. The latter may require a less intensive clinical surveillance for the early detection of neoplasia.