AIMS: The diagnosis of Hepatocellular carcinoma (HCC) is usually made late, precluding curative resection or liver transplantation in over 70% of HCC patients. P53 inducible gene 3 (PIG3) is a p53 downstream gene and a key component of the DNA damage response pathway, which is relevant in conditions with rapid cell turnover such as HCC. Our aim was to assess whether PIG3 could serve as a novel biomarker for HCC. METHODS: A pilot study of 37 consecutive patients with the diagnosis of HCC, 42 patients with hepatic cirrhosis versus healthy controlswas conducted. Serum AFP and PIG3 levels measured with enzyme-linked immunosorbent assay were compared across groups using student t-testand correlation coefficient (R) between AFP and PIG3 was calculated. RESULTS: Clinical characteristics were similar across the HCC and cirrhosis groups. Serum PIG3 levels were significantly higher among patients with cirrhosis or HCC (23.27±13.26 and 24.1±18.61 ng/ mL, respectively), as compared to healthy controls (3.71±1.79 ng/ mL, p<0.0001). PIG3 values were significantly different across the following tumor diameter ranges: less than 2 cm, 18.47 ng/mL; 2 to 5 cm, 18.54 ng/mL; and greater than 5 cm, 38.72 ng/mL; p=0.0012. The correlation coefficient between log (AFP) and PIG3 levels in HCC patients was r=0.4564, p=0.005. CONCLUSION: Serum p53-inducible gene 3 levels were significantly elevated in patients with HCC beyond 5 cm, indicating potential as an adjunct to imaging in determining eligibility for liver transplantation. The potential for PIG3 as a biomarker of HCC warrants further prospective study.