PURPOSE: To analyse diagnostic and therapeutic impact of molecular imaging TNM (miTNM) stage obtained with [F]DCFPyL versus [F]F-choline in head-to-head comparison in biochemical recurrence (BCR) of prostate cancer (PCa). MATERIAL AND METHODS: Patients with BCR of PCa after radical treatment with previous [F]F-choline-PET/CT (negative or oligometastatic disease) were recruited to [F]DCFPyL-PET/CT. Patients were classified according to: grade group, European Association of Urology classification, PSA, PSA doubling time (PSAdt) and PSA velocity (PSAvel). The overall detection rate (DR) and miTNM stage according to PROMISE criteria were assessed for both radiotracers and also correlated (Kappa). The influence of PSA and kinetics on both PET/CT (DR and miTNM) and predictive value of unfavourable kinetics on miTNM were determined. Cut-off PSA, PSAdt and PSAvel values able to predict PET/CT results were determined. Change in miTNM and treatment derived from [F]DCFPyL information compared with [F]F-choline were also evaluated. RESULTS: We studied 138 patients. [F]DCFPyL showed a higher DR than [F]F-choline (64.5% versus 33.3%) with a fair agreement. [F]DCFPyL and [F]F-choline detected T in 33.3% versus 19.6%, N in 27.5% versus 13.8%, and M in 30.4% versus 8.7%. Both tracers' DR showed significant associations with PSA and PSAvel. Significant association was only found between miTNM and PSA on [F]F-choline-PET/CT ( = 0.033). For [F]F-choline and [F]DCFPyL-PET/CT, a PSAdt cut-off of 4.09 and 5.59 months, respectively, were able to predict M stage. [F]DCFPyL changed therapeutic management in 40/138 patients. CONCLUSIONS: [F]DCFPyL provides a higher DR and superior miTNM staging than [F]F-choline in restaging BCR, especially with high PSA and unfavourable PSA kinetics, showing a fair agreement to [F]F-choline.