The aim of this phase II clinical trial (NCT02965001) was to evaluate the prognostic value of urokinase-type plasminogen activator receptor (uPAR) PET/CT with the novel ligand (68)Ga-NOTA-AE105 in head and neck cancer and compare it with (18)F-FDG. Methods: Patients with head and neck squamous cell carcinoma referred for curatively intended radiotherapy were eligible and prospectively included in this study. (68)Ga-uPAR and (18)F-FDG PET/CT were performed before initiation of curatively intended radiotherapy, and the SUV(max) of the primary tumor was measured on both PET/CT studies by 2 independent readers. Relapse-free survival (RFS) and overall survival (OS) were calculated, and optimal cutoffs were established for (68)Ga-uPAR and (18)F-FDG PET independently and compared using log rank and Kaplan–Meier statistics, as well as univariate and multivariate analysis in a Cox proportional-hazards model. Results: In total, 57 patients were included and followed for a median of 33.8 mo (range, 2.30–47.2, mo). The median SUV(max) of the primary tumors was 2.98 (range, 1.94–5.24) for (68)Ga-uPAR and 15.7 (range, 4.24–45.5) for (18)F-FDG. The optimal cutoffs for (68)Ga-NOTA-AE105 SUV(max) in the primary tumor were 2.63 for RFS and 2.66 for OS. A high uptake of (68)Ga-NOTA-AE105 (SUV(max) above cutoff) was significantly associated with poor RFS and OS (log-rank P = 0.012 and P = 0.022). (68)Ga-NOTA-AE105 uptake in the primary tumor was significantly associated with poor RFS in univariate analysis (hazard ratio [HR], 8.53 [95% CI, 1.12–64.7]; P = 0.038), and borderline-associated with OS (HR, 7.44 [95% CI, 0.98–56.4]; P = 0.052). For (18)F-FDG PET, the optimal cutoffs were 22.7 for RFS and 22.9 for OS. An (18)F-FDG SUV(max) above the cutoff was significantly associated with reduced RFS (log-rank P = 0.012) and OS (log-rank P = 0.000). (18)F-FDG uptake was significantly associated with reduced RFS (HR, 3.27 [95% CI, 1.237–8.66]; P = 0.017) and OS (HR, 7.10 [95% CI, 2.60–19.4]; P