With a NRI = −0.141 (p < 0.001) and IDI = −0.155 (p < 0.001) in the training cohort and NRI = 0.069 (p = 0.044) and IDI = 0.066 (p = 0.069) in the validation cohort, a combination of AFP RNAscope and GPC3 (AUC = 0.903 In the training cohort and AUC = 0.881 in the validation cohort) yielded improved performance in HCC detection compared to GPC3 alone (NRI = 0.063, p < 0.001 and IDI = 0.099, p < 0.001 in the training cohort, and NRI = 0.172, p < 0.001 and IDI = 0.215, p < 0.001 in the validation cohort). Here, AFP is linked to hepatocellular carcinoma.