The aim of the present study was to determine the diagnostic accuracy of different modes of fine needle aspiration (FNA) of liver lesions. A total of 492 FNAs were performed on 406 patients in order to confirm or to rule out focal or multifocal neoplastic disease: 29% under ultrasound (US) guidance, 3% with computed tomographic (CT) guidance, 67% preoperatively, and 1% intraoperatively without imaging guidance. Based on histologic, cytologic, and clinical findings, final diagnoses were reached in 387 patients, of whom 264 had malignant liver disease and 123 had benign liver disease. Of 321 aspirations performed in patients with malignant liver disease, the cytologic findings suggested malignancy in 225 (70.1%), suspected malignancy in 25 (7.8%), and did not reveal malignancy in 71 aspirations (22.1%). Among the 123 patients with benign liver disease, the cytologic findings were reported as benign in all but two patients, who had false-positive cytologic findings. The overall sensitivity, specificity, positive, and negative predictive values for cytologic findings were 85.6, 98.4, 99.1, and 76.1%, respectively. The overall diagnostic accuracy was 89.7%. In one patient, fatal intraperitoneal bleeding due to chronic intravascular coagulation complicated the FNA procedure. We conclude that imaging-guided FNA as well as nonguided FNA for cytologic diagnosis of liver lesions are highly accurate and only rarely may be associated with a fatal complication.