Objectives: The aim of our study was to evaluate the nature of focal liver lesions detected during the ultrasound follow-up of a population (prevalently anti-hepatitis C virus [anti-HCV] positive) with chronic liver disease., Methods: The study population consisted of 1827 consecutive newly diagnosed chronic liver disease cases without liver nodules at enrollment. Patients were screened at 4-month intervals by ultrasound and serum alpha-fetoprotein assessment. All lesions detected on imaging studies (except those accompanied by diagnostic a-fetoprotein levels) were subjected to biopsy (histology and cytology)., Results: During the 7-yr follow-up period (mean = 43.1 months), one or more solid focal lesions were found in 287 patients. a-Fetoprotein was diagnostic for hepatocellular carcinoma in 51 patients. Ultrasound-guided fine-needle biopsy was performed in the remaining 236 patients, yielding a diagnosis in 214: 198 hepatocellular carcinomas, 11 dysplastic nodules, and five B-cell non-Hodgkin's lymphomas (all confined to the liver and all in patients with chronic HCV infection). Twenty-two patients with nondiagnostic biopsies received diagnoses of hepatocellular carcinoma (20) or dysplastic nodules (two) based on arteriography or surgical biopsy., Conclusions: Focal lesions arising in patients with HCV-related chronic liver disease can be other than hepatocellular carcinoma, and ultrasound-guided fine-needle biopsy plays an important role in their diagnosis. The prevalence of non-Hodgkin's lymphoma in this selected population was 0.31%. The fact that all five lymphoma patients had cirrhosis related to hepatitis C strengthens the hypothesis of an etiological correlation between the latter infection and B-cell lymphoproliferative disorders.