Background Hepatocellular carcinoma (HCC) is the most frequent type of liver malignancy. For HCCs with low or normal alpha-fetoprotein (AFP), several indicators have been proposed. Aim To evaluate C-reactive protein (CRP) and platelet–lymphocyte ratio (PLR) as potential HCC markers. Patients and methods This was a cross-sectional study carried out at the Tropical Medicine Department of Tanta University. A total of 90 patients with cirrhosis owing to chronic hepatitis C were divided into group 1, which included 30 patients with HCC with low AFP; group 2, which included 30 patients with HCC with elevated AFP (>20 ng/ml); and group 3, which included 30 patients with liver cirrhosis (as control group). The PLR, CRP, and AFP were measured in each group. Results There were significant differences among the studied groups regarding CRP and AFP, with highest levels in group 2 and then group 1 and the least level in group 3. PLR showed significantly higher levels in group 3 when compared with group 2 and group 1. Conclusion CRP can differentiate patients with HCC in total and patients with HCC with low AFP from patients with cirrhosiswith high sensitivity and moderate specificity. When PLR is combined with CRP, the specificity is increased for the diagnosis of HCC cases from patients with cirrhosis.