Purpose <p>To investigate the clinical utility of [¹⁸F]FAPI-42 PET/CT relative to [¹⁸F]FDG PET/CT for tumor detection and staging in laryngeal squamous cell carcinoma (LSCC) patients.</p> Methods <p>Patients with pathologically proven LSCC were prospectively enrolled. All patients underwent [¹⁸F]FDG and [¹⁸F]FAPI-42 PET/CT within 1 week. Primary tumor and lymph node showed by [¹⁸F]FDG and [¹⁸F]FAPI-42 PET/CT were compared by SUVmax and visual assessment. The primary tumor volumes derived from [¹⁸F]FDG PET, [¹⁸F]FAPI-42 PET, and contrast-enhanced CT were also compared.</p> Results <p>Twenty-one patients were included from January to October 2024. [¹⁸F]FAPI-42 PET/CT has a higher positive detection rate of primary tumor than [¹⁸F]FDG (100% vs. 85.7%). For visual assessment of primary tumor invasion, [¹⁸F]FAPI-42 was superior to [¹⁸F]FDG in 9 of 21 patients (42.9%) and inferior to [¹⁸F]FDG in 1 patient (4.8%), which was confirmed by pathology. The diagnostic efficacy of [¹⁸F]FAPI-42 PET/CT for T staging was higher than that of [¹⁸F]FDG PET/CT (95.3% vs. 57.1%, <i>P</i> = 0.021). [¹⁸F]FAPI-42 led to downstaging of N stage in 4 of 21 patients (19.0%) relative to [¹⁸F]FDG PET/CT, which was consistent with pathology. Compared with [¹⁸F]FDG, [¹⁸F]FAPI-42 PET/CT changed overall staging in 10 of 21 patients, with 5 patients being up-staged and 5 down-staged. When 35% SUVmax of [¹⁸F]FDG or 40% SUVmax of [¹⁸F]FAPI-42 was used as a threshold for delineating tumor volume, it was highly consistent with contrast-enhanced CT.</p> Conclusion <p>[¹⁸F]FAPI-42 outperforms [¹⁸F]FDG in the tumor detection, staging, and the delineation of primary tumor, indicating that [¹⁸F]FAPI-42 PET/CT may serve as a promising imaging modality for detecting and staging patients with LSCC. Its value regarding distant metastases evaluation requires further investigation.</p> Trial registration <p>NCT06304155. <a href="https://clinicaltrials.gov/study/NCT06304155">https://clinicaltrials.gov/study/NCT06304155</a>.</p>