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Abstract Aberrant metabolisms have been hypothesized to precede the occurrence of hepatocellular carcinoma (HCC), therefore, we investigated biomarkers associated with subsequent HCC in peripheral bloods using metabolomic technologies. A cohort of 475 HCC-naïve liver cirrhotic patients were recruited and prospectively followed. A total of 39 patients developed HCC in the follow-up period. Baseline plasma metabolites were explored using untargeted nuclear magnetic resonance. Candidates were then quantified by ultra-performance liquid chromatography. A series of univairiate and multivariate analysis showed that Phenylalanine (Phe) and Glutamine (Gln) levels are associated with time to HCC, independent of viological etiologies and age. A HCC risk score R was then constructed using the polynomial combination of age, Phe and Gln in the units of micromolar (μM):$$\begin{aligned} {\text{R }} & = {\text{ Age }}* \, \left( {0.0694} \right) + {\text{ Phe }}* \, \left( {0.3399} \right) + {\text{ Phe }^{2}}* \, \left( { - 0.00188154} \right) \hfill \\ & \quad + {\text{ Gln }}* \, \left( { - 0.0133} \right) + {\text{ Gln }^{2}}* \, \left( { \, 0.00002244} \right) \hfill \\ \end{aligned}$$ R=Age∗0.0694+Phe∗0.3399+Phe2∗-0.00188154+Gln∗-0.0133+Gln2∗0.00002244 R correlates with the time to HCC significantly (Hazard ratio [HR] = 2.368, 95% confidence interval [CI] 1.760–3.187, P < 0.001). An additional cross-sectional analysis showed that Phe and Gln concentrations both correlates with HCC occurrence in the next 3 years (area under the receiver operating characteristic curve [AUC] = 0.607 and 0.629, P = 0.033 and 0.010 respectively). In conclusion, phenylalanine and glutamine concentrations in the peripheral blood correlate with subsequent HCC.