Background: Alpha-fetoprotein (AFP) is the most widely used biomarker for hepatocellular carcinoma (HCC) prognosis since it is expressed in the advanced stages of the disease. Consequently, AFP is not useful in establishing a prognosis for patients with a tumor in the early stages of the disease. hPG₈₀ (circulating progastrin), a new drug target for cancer treatment which plays a pivotal role in tumorigenesis, is present in the blood of multiple types of cancers at early stages including HCC. The purpose of this study was to evaluate the prognostic value of plasma hPG₈₀ in patients with HCC, in combination or not with AFP. Methods: A total of 168 HCC patients (BCLC from 0 to D) managed with local or systemic treatments, (“Liverpool” biobank) were enrolled prospectively and analyzed retrospectively. hPG₈₀ was quantified using DxPG₈₀ Lab kit (ECS-Progastrin) 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 survival was assessed using Kaplan-Meier curves and log-rank tests. Results: The median overall survival (OS) of the full cohort is 20.9 months. HCC patients with high hPG₈₀ levels (hPG₈₀+: >4.5 pM, 105/168) had significantly lower median OS compared to patients with low hPG₈₀ levels (hPG₈₀-: <4.5 pM, 63/168) (12.4 months versus undefined respectively, p < 0.0001). Patients with high AFP (AFP+: >100 ng/mL, 69/165) had significantly lower median OS compared to patients with low AFP (AFP: <100 ng/mL 96/165) (7.2 months versus undefined, p < 0.0001). To improve the stratification, the patients were further categorized into four groups: hPG₈₀-/AFP- (n = 42), hPG₈₀+/AFP- (n = 54), hPG₈₀-/AFP+ (n = 21) and hPG₈₀+/AFP+ (n = 48). In the AFP- group, hPG₈₀+ patients exhibited a significantly worse prognosis than those with hPG₈₀- (26.3 months versus undefined, p=0.0087). Similarly, in the AFP+ group, patients with hPG₈₀+ had a significantly worse survival compared to hPG₈₀- patients (5.7 months versus 13.4 months, p = 0.0391). Finally, we evaluated the median OS of AFP+ patients according to BCLC staging. Interestingly, in the group BCLC 0 to B, hPG80+ had a significantly worse prognosis than those with hPG₈₀- (15.8 months versus 40.25 months, p=0.0317). Conclusions: Our findings show that hPG₈₀ could serve as a new prognostic biomarker in HCC. Used in combination with AFP, it improves the stratification of the patients in good and worst prognosis, especially for those patients with negative AFP and early-stage HCC.