Intraoperative ultrasonography (IOUS) is the most accurate diagnostic technique for staging hepatocellular carcinoma (HCC), but has low accuracy in differentiating the new nodules detected in the cirrhotic liver. The aim of this preliminary report is to evaluate whether contrast-enhanced intraoperative ultrasonography (CE-IOUS) could provide additional information to IOUS in patients with HCC. From August 2002 to July 2003, a prospective validation cohort study was conducted. For this purpose, 16 consecutive patients underwent liver resection for HCC using IOUS and CE-IOUS. Intraoperatively, in all patients 4.8 mL of SonoVue was injected intravenously through a peripheral vein. IOUS depicted 16 new focal liver lesions: 10 with no enhancement peculiar to HCC at CE-IOUS pattern and at histology (4) or imaging follow-up (6) proved to be benign; the remaining 6 had enhancement peculiar to HCC and histology confirmed this diagnosis. Two different patterns of enhancement were also recognized at CE-IOUS in those HCC nodules depicted preoperatively: one had no similarity to that observed at CT. CE-IOUS added findings to those of unenhanced IOUS in 50% of patients. These results show that IOUS accuracy and specificity is improved by CE-IOUS, with a great impact on surgical strategy and oncological radicality. Furthermore, a wider experience with vascular enhancement patterns with CE-IOUS could provide a new classification for HCC nodules.