OBJECTIVE To investigate the value of CT spectral imaging in differentiating hepatocellular carcinoma (HCC) from focal nodular hyperplasia (FNH) during the arterial phase (AP) and portal venous phase (PP). METHODS Fifty-eight patients with 42 HCCs and 16 FNHs underwent spectral CT during AP and PP. The lesion-liver contrast-to-noise ratio (CNR) at different energy levels, normalised iodine concentrations (NIC) and the lesion-normal parenchyma iodine concentration ratio (LNR) were calculated. The two-sample t test compared quantitative parameters. Two readers qualitatively assessed lesion types according to imaging features. Sensitivity and specificity of the qualitative and quantitative studies were compared. RESULTS In general, CNRs at low energy levels (40-70 keV) were higher than those at high energy levels (80-140 keV). NICs and LNRs for HCC differed significantly from those of FNH: mean NICs were 0.25 mg/mL ± 0.08 versus 0.42 mg/mL ± 0.12 in AP and 0.52 mg/mL ± 0.14 versus 0.86 mg/mL ± 0.18 in PP. Mean LNRs were 2.97 ± 0.50 versus 6.15 ± 0.62 in AP and 0.99 ± 0.12 versus 1.22 ± 0.26 in PP. NICs and LNRs for HCC were lower than those of FNH. LNR in AP had the highest sensitivity and specificity in differentiating HCC from FNH. CONCLUSIONS CT spectral imaging may help to increase detectability of lesions and accuracy of differentiating HCC from FNH. CONCLUSIONS • CT spectral imaging may help to detect hepatocellular carcinoma (HCC). • CT spectral imaging may help differentiate HCC from focal nodular hyperplasia. • Quantitative analysis of iodine concentration provides greater diagnostic confidence. • Treatment can be given with greater confidence.