Objectives <p>To assess the prognostic value of Fluorine 18-labeled fluorodeoxyglucose [¹⁸F]FDG, gallium 68-labeled fibroblast-activation protein inhibitor-04 [⁶⁸Ga]Ga-FAPI-04, ¹¹C-acetate in hepatocellular carcinoma (HCC) and evaluate the potential usefulness and advantages of different combinations for accurate diagnosis.</p> Materials and methods <p>Thirty-six patients with suspected hepatic masses were prospectively enrolled from May 2021 to September 2022 and underwent [¹⁸F]FDG, [⁶⁸Ga]Ga-FAPI-04, and ¹¹C-acetate PET/CT scans before surgery. PET/CT results and histopathologic examinations were independently interpreted by two radiologists and pathologists, respectively. Kaplan–Meier overall survival curves were calculated and the sensitivity among [¹⁸F]FDG, ¹¹C-acetate, [⁶⁸Ga]Ga-FAPI-04, and different combinations were compared.</p> Results <p>Of the 36 included patients (mean age, 59 years ± 10 (standard deviation)), 29 were diagnosed with HCC, four with non-HCC malignant tumors, and three with benign tumors. Patients with HCC lesions negative for ¹¹C-acetate or [⁶⁸Ga]Ga-FAPI-04 exhibited poorer overall survival. Out of 36 patients, 44 HCC lesions were detected. The dual-tracer [⁶⁸Ga]Ga-FAPI-04/¹¹C-acetate exhibited the highest sensitivity (39 of 44 lesions (88.6%)) among all schemes. HCC lesions with higher histological grade and microvascular invasion (MVI) showed higher maximum standardized uptake value (SUV_max) and tumor-to-background ratio (TBR) of [¹⁸F]FDG, but no evidence of significant differences was found in [⁶⁸Ga]Ga-FAPI-04 and ¹¹C-acetate PET/CT. Higher expression of fibroblast activation protein (FAP) showed higher uptake of [⁶⁸Ga]Ga-FAPI-04 and [¹⁸F]FDG.</p> Conclusion <p>[⁶⁸Ga]Ga-FAPI-04 and ¹¹C-acetate PET/CT exhibited good predictive value for HCC patients, with their combination showing the highest sensitivity for HCC detection, suggesting potential for improved diagnostic protocols.</p> Key Points <p><Emphasis Type="BoldItalic">Question</Emphasis> <i>What are the prognostic and diagnostic values of PET/CT tracers, including</i> [^<i>18</i><i>F]FDG</i>, [^<i>68</i><i>Ga]FAPI-04, and</i> ^<i>11</i><i>C-acetate?</i></p> <p><Emphasis Type="BoldItalic">Findings</Emphasis> <i>Hepatocellular carcinoma, with differing findings across</i> [^<i>18</i><i>F]FDG,</i> [^<i>68</i><i>Ga]GaFAPI-04, and</i> ^<i>11</i><i>C-acetate PET/CT, showed varied prognoses</i>; [^<i>68</i><i>Ga]GaFAPI-04 and</i> ^<i>11</i><i>C-acetate combined offered the highest detection sensitivity.</i></p> <p><Emphasis Type="BoldItalic">Clinical relevance</Emphasis> <i>Evaluating the prognostic value and diagnostic efficacy of different tracer combinations in patients with hepatocellular carcinoma helps to guide the optimal selection of tracers in clinical practice.</i></p>