To determine the feasibility of spectral computed tomography (CT) in the differentiation of focal liver lesions from hepatocellular carcinoma (HCC) using a network meta-analysis (NMA). The review was completed in accordance with PRISMA guidelines. Searches of three medical databases were performed. A total of nine articles were found for the qualitative synthesis. The meta-analysis was performed on five studies for the normalised iodine concentration (NIC; which is the iodine concentration in the lesion divided by the iodine concentration in the aorta) and the lesion-normal parenchyma iodine ratio (LNR; which is the iodine concentration in the lesion divided by the iodine concentration in the non-tumour hepatic parenchyma) on portal venous and arterial phase images due to sufficient data. Spectral CT can be used to differentiate HCC from hepatic haemangioma (HH), focal nodular hyperplasia (FNH), regenerative nodules, neuroendocrine tumours (NETs), abscesses, and angiomyolipoma (AML). Hepatic metastases versus abscess and FNH versus HH could also be differentiated. The NMA demonstrated that HCC, NETs, and regenerative nodules could be differentiated due to lower quantitative iodine values. FNH, AML, and HH all had higher values. Spectral CT shows promise in differentiating focal liver lesions. Studies with larger sample sizes are warranted. Future studies should be performed comparing benign lesions using quantitative markers.