Hepatocellular carcinoma (HCC) is a tumor with the most rapid increase in incidence in the United States and this trend is expected to continue over the next 2 decades. It is a deadly tumor with only about 10% patients eligible for curative intervention transplantation or surgical resection). The incidence and death rates of HCC are equal because current tools for the diagnosis of HCC: alpha-fetoprotein (AFP) and ultrasound lack sensitivity and specificity. Therefore, strategies to improve the early detection and to identify those at the highest risk are of paramount importance. This proposal is centered on the validation of novel serum markers for the diagnosis of early HCC. Two studies will be conducted: a case-control study and a prospective cohort study. The case-control study will enroll patients presenting with HCC as cases and patients in the cirrhosis cohort study, who have not developed HCC as controls. Early HCC includes stage I and II HCC according to UNOS TNM system. Preliminary studies showed that des-gamma carboxyprothrombin (DCP), alone or in combination with a novel Golgi Protein-73 (GP73) are more sensitive and specific in the diagnosis of HCC but very few patients with early HCC were included. In this proposal, I will determine if DCP, GP73, and other novel serum markers identified through proteomics, alone or in combination will be more sensitive and specific than AFP in the diagnosis of early HCC. The prospective cohort study will enroll patients with cirrhosis and no HCC followed every 6 months for up to 54 months to determine if DCP, GP73 and other serum markers can lead to the diagnosis of HCC earlier. Demographics, medical history, tobacco and alcohol use, and laboratory data will be obtained to examine risk factors associated with HCC development. My career goal is to be an independently successful clinical investigator focused on early detection of HCC. I recognize that to achieve my goal, additional didactic training and experience in design and conduct of clinical studies under the guidance of accomplished mentors will be crucial. The K23 award will provide the protected time that is critical to my success. During the funding period, I will pursue additional courses in statistics and epidemiology. I will supervise the conduct of the proposed research and meet with my mentors and advisors regularly. Completing this proposal will allow me to achieve my career goal and to contribute to an improve outcome of patients with HCC.