Purpose <p>Tumor-associated neovasculature and energy metabolism reprogramming serve as critical indicators of tumor proliferation, progression, invasion, and metastasis. This study conducted a head-to-head clinical investigation and comparison of [¹⁸F]FDG and [⁶⁸Ga]Ga-HX01 PET by reflecting neovasculature and glucose metabolism in sarcoma patients, respectively.</p> Methods <p>We reviewed the imaging data of sarcoma patients who underwent [⁶⁸Ga]Ga-HX01 PET/MR and [¹⁸F]FDG PET/CT from June 29, 2022, to December 21, 2023. The two imaging modalities were performed on two separate days within one week of each other. A cohort of 21 patients with an average age of 45.81 ± 19.99 years were enrolled. The location, number and PET characteristics of all lesions were collected. The relationships between the two tracers were evaluated.</p> Results <p>Among the 21 patients, 4 underwent imaging for initial disease staging, while the remaining 17 were imaged to detect recurrences. Patient-based analysis revealed that [⁶⁸Ga]Ga-HX01 PET/MR diagnostic performance was equivalent to [¹⁸F]FDG PET/CT in lesion detection (<i>P</i> = 1.0). The SUVmax value of [⁶⁸Ga]Ga-HX01 (4.64 ± 1.90) was significantly lower than that of [¹⁸F]FDG (9.43 ± 6.17, <i>P</i> = 0.002) across all patients. In terms of lesion-based analysis, [⁶⁸Ga]Ga-HX01 identified two additional lesions compared to [¹⁸F]FDG, though this difference was not statistically significant (94 vs. 92, <i>P</i> = 0.678). The SUVmax value for all lesions with [⁶⁸Ga]Ga-HX01 (3.47 ± 1.68) was also lower than that with [¹⁸F]FDG (5.82 ± 4.81, <i>P</i> = 0.003). Notably, [⁶⁸Ga]Ga-HX01 was preferred in patients receiving hematopoietic cytokines.</p> Conclusion <p>[⁶⁸Ga]Ga-HX01 PET offers comparable diagnostic efficacy to [¹⁸F]FDG PET/CT in sarcoma, with potential advantages in specific clinical scenarios. Larger cohorts are needed to validate these findings.</p> Clinical Trial Registration <p>NCT05490849 and NCT06416774.</p>