ABSTRACT Hepatocellular carcinoma (HCC) accounts for 80 to 90% of primary liver cancer. It is the fifth most common malignancy and is the third most common cause of cancer-related death. This application will test the novel approach of antivascular ultrasound for treating HCC. Our preliminary studies show that low- level ultrasound with intensities comparable to those used in treating physiotherapy patients, when used with microbubbles, disrupts tumor neovasculature and improves the survival of animals with implanted tumors. The goals of the research are to demonstrate the efficacy of antivascular ultrasound for treating HCC, and to identify the conditions of treatment that have high efficacy as measured both by imaging and survival of the animals with implanted liver tumors. The proposal has three Specific Aims. Specific Aim 1 will investigate the relationship between blood flow and temperature change. Specific Aim 2 will determine the ultrasound exposure conditions that produce tumor antivascular activity at the lowest possible exposure to ultrasound. Specific Aim 3 will evaluate the short-term and the long term-term therapeutic efficacy of single and multiple ultrasound treatments. We anticipate that the knowledge gained from the proposed research will lead to a new form of antivascular or vascular disrupting treatment for HCC. Of particular interest would be the ability of antivascular ultrasound to treat non-resectable small and large cancers frequently observed clinical. Advantages include the simplicity and small cost of low-intensity ultrasound technology, the use of quantitative ultrasound imaging to assess and monitor therapeutic efficacy at the time of treatment, and fewer unwanted side effects from the low-intensity ultrasound therapy compared to cytotoxic therapies. We anticipate that the results of this study will facilitate the translation of a novel ultrasound technology to the treatment of patients with HCC.