Abstract Background Hepatocellular Carcinoma (HCC) is a common malignancy occurring globally but with a dismal prognosis. Des-gamma-carboxyprothrombin (DCP) has been reported to be more sensitive and specific than Alpha-fetoprotein (AFP) in the diagnosis of HCC among the White population. Its efficacy among the Black population is yet to be established. The aim of this study therefore, was to determine the relative sensitivity and specificity of des-gamma-carboxyprothrombin and alpha-fetoprotein in the diagnosis of hepatocellular carcinoma in a cohort of Nigerian patients presenting at a single referral centre. Methods Cross-sectional case–control study was carried out using 62 HCC patients and 57 controls with benign liver diseases including chronic hepatitis and compensated liver cirrhosis. Both DCP and AFP were tested using enzyme immunoassay methods. Results Sixty-nine percent of the HCC patients presented with tumour sizes >5 cm while 31 % presented with tumour sizes 3-5 cm. No patient presented with tumour sizes 140mAU/ml. Similarly, the sensitivity and specificity of AFP were 62.9 % and 93.3 % at an ROC - derived optimum cut-off level of 18mAU/ml. The area under the receiver operating characteristic curve (AUROC) for DCP was 0.99 and was significantly larger than that of AFP which was 0.85 ( p