Imaging techniques like ultrasonography (US) or computed tomography (CT) allow full liver scanning and the accurate detection of focal lesions of the liver parenchyma. The occurrence of such lesions in concomitance with non-Hodgkin's lymphoma (NHL), both at the onset of the disease and during follow-up, is of great significance, because it affects staging, prognosis and therapeutic choices. Moreover, the occurrence of focal liver lesions in the setting of a lymphoma is generally considered to be a marker of liver involvement. Nonetheless, data on the prevalence and clinical significance of focal liver lesions occurring in these clinical conditions are limited. Therefore, we retrospectively evaluated the prevalence, nature and clinical significance of focal liver lesions diagnosed by imaging techniques (US and CT) in 414 consecutive NHL patients. The nature of the lesions was established either by US-guided biopsy or by evaluation of the response to chemotherapy for the underlying disease and confirmed by clinical and US follow-up. Subtype of NHL (aggressive or indolent) and Hepatitis C virus (HCV) status were also considered. We detected 129 focal liver lesions (76 at onset and 53 during the follow-up). Hepatic involvement by NHL was found in 69 cases (53%). We observed 7 cases of Hepatocellular Carcinoma (HCC) and 3 cases of metastasis. At onset, only 39% of the detected lesions were due to lymphoma and 58% were benign. Conversely, 74% of the liver lesions detected during the follow-up were due to NHL while 15% to a malignancy other than NHL. All HCC cases occurred in HCV-positive patients with chronic liver disease. We concluded that the focal liver lesions detected at onset in NHL patients are frequently benign and unrelated to the underlying disease. Conversely, most focal liver lesions detected during the follow-up period are malignant and the possibility of HCC occurrence in HCV-positive patients should always be considered. Therefore, these lesions should undergo a full diagnostic work-up, including US-guided biopsy.