Background: Positron emission tomography/x−ray computed tomography (PET/CT) utilizing radiotracers targeting prostate membrane specific antigen (PSMA) offer the promise of improved sensitivity for visualizing low volume sites of prostate cancer. In this study we evaluated the sensitivity of PET/CT using ¹⁸F-DCFPyL, a novel small molecule ligand of PSMA, for imaging sites of disease in men with an elevated PSA following radical prostatectomy. Methods: Patients with an elevated PSA following radical prostatectomy (defined as ≥ 0.2 ng/mL) were imaged with CT or magnetic resonance imaging (MRI) of the abdomen and pelvis, ^99mTc-methylene diphosphonate bone scan and ¹⁸F-DCFPyL PET/CT. Conventional imaging studies (CT, MRI and boen scan) were clinically reviewed by readers blinded to the PET/CT scan results. Similarly, PET/CT scans were blindly reviewed and then the sensitivity of this novel imaging test was compared to that of conventional imaging. Results: In total, 12 men with a median PSA of 0.34 ng/mL (range 0.2 to 11) were imaged as part of this study. 2 (16.7%) patients had persistently elevated PSA values after surgery and 10 (83.3%) had values which were initially undetectable but then rose to ≥ 0.2 ng/mL. On conventional imaging, only 4 (25.0%) patients had at least 1 detectable site of disease. This included 1 patient with a local recurrence detected on MRI and 3 patients with bony lesions detected on bone scan. In contrast, 9 (75.0%) patients had areas of detectable disease on PET/CT. This included 3 (25.0%) patients with a local recurrence, 3 (25.0%) with lymph node metastases, 2 (16.7%) with bony lesions and 1 (8.3%) with both lymph node and bone findings. All lesions detected on conventional imaging had corresponding areas of radiotracer uptake on PET/CT. Conclusions: ¹⁸F-DCFPyL PET/CT appears to be more sensitive for detecting areas of prostate cancer recurrence in patients with an elevated PSA following radical prostatectomy. Future work aims to more precisely define the sensitivity of this imaging test in a larger patient cohort. Clinical trial information: NCT02523924