Hepatocellular carcinogenesis in cirrhosis is a multistage process that includes large regenerative nodules, dysplastic nodules, and hepatocarcinoma. The aim of this study was to establish whether contrast-enhanced Doppler ultrasonography (US) is able to distinguish between early hepatocellular carcinoma (HCC) and small nonmalignant nodules in cirrhosis. Between January 1998 and December 1999, 500 cirrhotic patients with no previous history of HCC or evidence of hepatic focal lesions were enrolled and prospectively followed-up with US every 6 months until December 2000. Sixty-one patients developed focal lesions, 12 multifocal, and 49 monofocal. Biopsy of focal lesions, contrast-enhanced Doppler US, and spiral computed tomography (CT) were performed in 41 consecutive patients with small (<3 cm) monofocal lesions. Twenty nodules were diagnosed as HCC and 21 as nonmalignant (14 large regenerative nodules, 3 low-grade, and 4 high-grade dysplastic nodules) by liver biopsy. Intratumoral arterial blood flow was detected in 19 of 20 (95%) HCC and 6 of 21 (28%) nonmalignant nodules by contrast-enhanced Doppler US (P<.0001). The mean peak resistance and pulsatility indices were 0.82 +/- 0.09 and 1.56 +/- 0.2 in HCC and 0.62 +/- 0.08 and 0.82 +/- 0.08 in dysplastic lesions (P =.002 and.0001), respectively. Spiral CT revealed arterial perfusion in 19 of 20 HCC and in 4 of 21 nonmalignant nodules (high-grade dysplastic nodules). Four of the apparently false-positive nodules at enhanced Doppler US were high-grade dysplastic nodules and 2 evolved to HCC during follow-up. In conclusion, contrast-enhanced Doppler US is a noninvasive, very sensitive technique in differentiating malignant and premalignant lesions from nonmalignant focal lesions in the liver.