Cancer is one of the leading causes of death in both economically developed and developing countries. Among all the cancers, hepatocellular carcinoma (HCC) was a significant contributor being the fifth most prevalent and third leading global cause of deaths related to cancer. The most common biomarker use in its detection is Alpha-fetoprotein (AFP), but it has low sensitivity and specificity. Many other biomarkers have been evaluated for HCC detection, of which Protein Induced by Vitamin K Absence-II (PIVKA-II) is one, that showed elevated levels in these patients. So, we tried to evaluate the role of PIVKA-II in diagnosing HCC and its usefulness in differentiating HCC and Hepatic Cirrhosis (HC). The study group consisted of 70 patients with liver disease- 35 with HCC, 35 with cirrhosis; and 20 healthy study subjects who were age and gender matched. All patients and healthy subjects were evaluated for serum levels of both PIVKA-II and AFP. The median serum concentration of PIVKA-II in HCC, HC patients and healthy subjects were found to be 40.37 (23.3–79.38) ng/mL, 2.33 (1.03–3.72) ng/mL and 2.27 (0.12–12.87) ng/mL, respectively. To assess diagnostic utility, Receiver operating characteristic (ROC) curves plotted for both PIVKA-II and AFP. At a cut-off level of 6.715 ng/mL, PIVKA-II showed 85.71% sensitivity and 95.0% specificity, whereas AFP at a cut-off level of 11.8 ng/mL showed 77.14% sensitivity and 95% specificity. When both combined, their sensitivity increased to 94.29%. Also, there was a positive correlation of PIVKA-II levels with tumor size (p = 0.043), while no such significant association was found with AFP. Therefore, our study concludes that PIVKA-II is more sensitive than AFP in diagnosing HCC and differentiating it from Hepatic Cirrhosis; and when both combined, the sensitivity increased. Also, the positive correlation of Tumour size with PIVKA-II levels indicates that it may be useful in monitoring patients for progression of HCC.