Accurate staging is necessary in hepatocellular carcinoma (HCC) patients to choose the most appropriate therapeutic approach. In the present study, 50 patients with one or more HCC lesions were prospectively examined with ultrasonography (US), Computed Tomography (CT), Magnetic Resonance Imaging (MRI), digital subtraction angiography (DSA) and CT after intraarterial injection of Lipiodol (Lipiodol CT). The study was aimed at suggesting the most appropriate diagnostic work-up for HCC staging. A hundred and twenty-one HCC lesions were detected in the 50 examined patients by means of the above imaging techniques: namely, 21 patients had single lesions, 15 had two lesions, 4 had three lesions and 10 patients had more than three lesions (range: 4-12). US detected 98/121 lesions (81%), CT 92/121 (76%), MRI 90/121 (74%), DSA 102/121 (84%) and Lipiodol CT 115/121 lesions (95%). The sensitivity of Lipiodol CT was significantly higher than that of all the other imaging techniques (p < 0.05). The detection rate of each technique was correlated with the size of the tumors, which were divided into three groups: lesions < or = 1 cm (no. 28), lesions ranging 1.1 to 3 cm (no. 43) and lesions > 3 cm (no. 50). In the lesions < or = 1 cm, detection rates ranged 29-93%; in this group a statistically significant difference (p < 0.01) was observed between Lipiodol CT and all the other imaging modalities. In the lesions 1.1-3 cm, detection rates ranged 77-93%; in this group a statistically significant difference (p < 0.05) was observed between Lipiodol CT and MRI. In the lesions > 3 cm, sensitivity was very high for all imaging modalities--i.e., 94% or higher; in this group no statistically significant difference was observed among the various imaging modalities. Combined US and CT detected 104/121 lesions (86%), US and MRI 101/121 (83%) and CT and MRI 98/121 (81%). The combination of US, CT and MRI allowed the detection of 107/121 lesions (88%), which markedly improved the results of US alone (the statistical index was just above the one usually considered to be significant). In conclusion, our data suggest the following staging work-up for HCC: (a) US as the first step diagnostic tool; (b) CT and possibly MRI, in the cases with a single lesion at US and in the patients eligible for surgery; (c) Lipiodol CT in the cases which CT and MRI confirmed to be single lesions.