BackgroundNeopetrin is a biological marker for increased cell-mediated immunity; serum neopterin level is increased in patients with hepatocellular carcinoma (HCC) as well as in patients with tumors metastasizing to the liver. Aim of the work The present study aimed to evaluate the significance of serum neopterin as a potential marker for HCC compared with alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II). Patients and methodsThe present study was carried out on 80 patients, 40 HCC patients and 20 patients with liver cirrhosis, in addition to 20 apparently healthy individuals who served as a control group. The serum levels of AFP, PIVKA-II, and neopterin were measured for all cases as well as liver function tests and viral markers. ResultsSerum level of neopterin was significantly elevated in HCC patients compared with the cirrhotic and control groups. Receiver-operating characteristic curves analysis indicated that the best cut-off value for the detection of HCC patients was 24.2 ng/ml for AFP, with a sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of 72.5, 75, 75.8, 72.1, and 73.8%, respectively, for PIVKA-II, it was 4.1 ng/ml, with a sensitivity, specificity, PPV, NPV, and accuracy of 72.5, 95, 95.9, 74.8, and 83.7% respectively, and for neopterin, it was 12.8 nmol/with a sensitivity, specificity, PPV, NPV, and accuracy of 95.0, 80, 81.7, 93.7, and 87.5%, respectively. The best combination was neopterin and PIVKA-II (with a sensitivity, NPV, and overall accuracy of 97.5, 97, and 88.8%, respectively). Conclusion Serum neopterin is a sensitive marker for HCC and can be used in the detection of patients with early-stage HCC. When used with PIVKA-II, high levels of sensitivity and NPV may be possible.