Postoperative recurrence of hepatocellular carcinoma (HCC) is presented as local recurrence (LR) or extrahepatic metastasis (EHM). Recent studies indicated that EHM requires additional cellular alterations. This study aimed to examine the clinical and molecular prognostic predictors of these two events. HCC patients (289) [training cohort (n=160) and verification cohort (n=129)] receiving surgical resection of hepatomas were included. The expression levels of six signaling molecules were quantitatively assessed for prognostic analysis. Clustering analysis revealed similar expression profiles between cancer (T) and non-cancer (N) liver tissues in the same individuals. Univariate analysis showed that phosphorylated mammalian target of rapamycin (mTOR)-T was associated with LR-free survival (P=0.002), whereas extracellular signal-related kinase (ERK2)-T (P=0.005), AKT-T (P=0.001) and glycogen synthase kinase (GSK)-T/N ratio (P=0.008) were associated with EHM-free survival. When clinical predictors were added for multivariate analysis, only prolonged prothrombin time (P=0.003) and tumor number (P=0.031) was independently associated with LR-free survival, whereas age (P=0.019), creatinine levels (P=0.001) and AKT-T (P=0.004) were associated with EHM-free survival. These factors were further examined in the verification cohort. In conclusion, postoperative LR and EHM in HCC were associated with separable sets of clinical and molecular predictors.