Background: Alpha-fetoprotein (AFP) is the most widely used biomarker for hepatocellular carcinoma (HCC) prognosis. However, AFP is not useful in establishing a prognosis for patients with a tumor in the early stages. hPG₈₀ (circulating progastrin) is a tumor promoting peptide present in the blood of patients with various cancers including HCC, even at early stages. In this study, we evaluated the prognostic value of plasma hPG₈₀ in patients with HCC at early and intermediate stages. Methods: A total of 79 HCC patients including 44 BCLC from 0 to A and 35 BCLC B managed with local or systemic treatments, (“Liverpool” biobank) were enrolled prospectively and analyzed retrospectively. hPG₈₀ was quantified using DxPG₈₀ Lab kit (ECS-Progastrin) with a limit of detection at 1 pM and AFP was quantified using Cobas E411 in the blood of HCC patients. An optimal cutoff value of hPG₈₀ was identified at 4.5 pM by calculating the minimal p-value based on the log-rank method. For AFP, a cutoff of 100 ng/mL was used as for liver transplantation (Notarpaolo, 2016). The prognostic impact of hPG₈₀ and AFP levels on patient overall survival (OS) was assessed using Kaplan-Meier curves and log-rank tests. Results: hPG₈₀ was detected in 36 of 44 (81.8%) HCC patients at stages BCLC 0 to A and 29 of 35 (82.9%) at stage BCLC B by contrast to AFP present in only 5 (11.4%) and 9 (25.7%) patients respectively. The median of hPG₈₀ was 5.7 pM (IQR: 1.7-22.4 pM) at stages BCLC 0 to A, 6.0 pM (IQR: 1.5-22.2 pM) at stage BCLC B and significantly different from a non-HCC age-range matched control group cohort (median value: 1.5 pM, IQR 0.6-3.2 pM, p < 0.0001). When combining BCLC 0 to B, the median OS for hPG₈₀+ patients (n = 46) was significantly shorter than that of hPG₈₀- patients (n = 33) (25 months versus undefined, HR: 3.07, 95% CI: 1.46-6.43; p = 0.0064). AFP+ patients were also significantly correlated with poorer OS (17.5 months versus undefined, HR: 3.16, 95% CI: 1.06-9.47; p = 0.0030). Then, we evaluated the prognostic significance of hPG₈₀ in combination with AFP levels. hPG₈₀+ patients with AFP > 100 ng/mL (n = 46) had a worse OS than that of patients with AFP < 100 ng/mL patients (n = 33) (15.8 months versus undefined, HR: 6.38, 95% CI: 1.74-23.41; p = 0.0052). Conclusions: Our findings show that hPG₈₀ could serve as a new prognostic biomarker for HCC patients at early to intermediate stages. These results will need to be confirmed in a prospective study, but it opens the possibility to use hPG₈₀ as a biomarker for HCC patients at early stage at a time they can be treated to be cured.