The aim of this study is to clarify the usefulness of defect reperfusion ultrasound (US) imaging using Sonazoid in the management of hepatocellular carcinoma (HCC). A total of 33 HCC nodules and 34 local recurring nodules after radiofrequency ablation (RFA), which could not be identified by B-mode US but were depicted by dynamic CT, were studied by defect reperfusion US imaging with Sonazoid. In addition, Kupffer phase Sonazoid-enhanced US in combination with defect reperfusion US imaging were used for screening HCC in 262 consecutive cirrhotic patients. As a result, 33 US undetectable HCC nodules and 34 local recurring HCC nodules were successfully confirmed by Sonazoid-enhanced US with defect reperfusion imaging. Subsequently, RFA was successfully performed in all of 67 HCC nodules with a Sonazoid-enhanced US guidance. A total of 7 small HCCs were depicted and confirmed as HCCs by Kupffer phase surveillance and defect reperfusion US imaging. In conclusion, defect reperfusion US imaging is extremely useful in the depiction and confirmation of US undetectable HCCs as well as in the surveillance of HCC in cirrhotic patients.