As the sixth most common cancer and the third most common cause of cancer death accounting for 800,000 deaths a year globally, hepatocellular carcinoma (HCC) is a challenging malignancy to diagnose and manage, with an overall 5-year survival of only 20%. HCC has a rising incidence and is the leading cause of death among patients with cirrhosis. Since liver cancer is found more frequently among men, and death related to liver cancer is about 3 times greater in men, the United States veteran population is at particular risk. Veterans have a higher incidence of nonalcoholic fatty liver disease, alcohol associated liver disease and viral hepatitis, which are the most common risk for HCC. The threat of HCC persists despite the successful cure of hepatitis C infection. The VA Health Care System is the largest provider in the US for the treatment of liver disease and liver cancer, thus making advances in detection, diagnosis, radiogenomics and the identification of prognostic indicators of liver cancer an important component of the VA’s Precision Oncology initiative. Prostate-specific membrane antigen (PSMA) is upregulated in an estimated 91% of HCC. Preliminary studies have shown that a novel PSMA-targeted PET (PSMA PET), which is currently approved and utilized for the evaluation of prostate cancer, is highly sensitive in the detection of HCC. In this proposal, we delineate a plan to consider and demonstrate the utility of PSMA PET scans in three groups of veterans: those undergoing surveillance for HCC, treatment naïve patients who are newly diagnosed with HCC, and patients previously treated for HCC being evaluated for treatment response. By evaluating PSMA PET in these specific patient populations, we intend to improve the accuracy of diagnosis and staging of HCC, and avoid futile locoregional therapies to patients with metastatic HCC. By improving the diagnosis and staging of HCC with PSMA-PET the ultimate aim of this study is improved overall survival. Specifically, the following parameters will be evaluated: 1. the utility of PSMA PET in improving the diagnosis of HCC within indeterminate nodules (LIRADS; LR3 and LR4 lesions) in patients with cirrhosis undergoing surveillance, 2. the addition of PSMA PET in improving the accuracy of HCC staging among treatment naïve patients compared to CT/MRI, 3. the role of PSMA PET in improving the assessment of treatment response in HCC patients treated with locoregional therapy (LRT). We expect that PSMA PET will identify locoregional or distant HCC metastatic lesions not detected by CT/MRI, thus altering BCLC staging and management. We also anticipate that the lack of uptake of PSMA may reliably detect the complete response of HCC after LRT, and that residual activity will correlate with viable tumor. PSMA PET will be performed concurrently with CT/MRI, and staging and response to HCC treatment will be compared between that with CT/MRI, and CT/MRI plus PSMA PET. Data gathered by this observational clinic...