The usefulness of ultrasound and echo-guided fine-needle biopsy (FNB) in the diagnosis of focal fatty liver change (FFLC) is stressed, on the basis of a retrospective series of 21 patients (8 of whom with a past history of primary cancer), followed-up for a mean period of 13.7 months. FFLC presented with various echographic patterns, shapes, dimensions and localizations. In 17 patients the diagnosis of FFLC was made by FNB, yielding cytologic and/or histological samples with steatotic, but also normal, hepatocytes. In another 4 patients the diagnosis was made by echographic follow-up. In all patients, clinical, hematological and echographic follow-up excluded the onset of neoplastic disease, confirming the high specificity of FNB in diagnosing FFLC. The possibility of changing appearance over time, and the inconstant correlation of FFLC with known causes of hepatic steatosis are discussed, as well as the hypothesis that the focal defect seen with ultrasound, could be an area of normal hepatic tissue in a fatty liver. The authors affirm the necessity to perform FNB on each doubtful lesion, but certainly when the patient has a history of malignancy.