Description: In prostate cancer with biochemical failure after therapy, current imaging techniques have a low detection rate at the prostate-specific antigen (PSA) levels at which targeted salvage therapy is effective. 11 C-choline and 18 F-fluoromethylcholine, though widely used, have poor sensitivity at low PSA levels. 68 Ga-PSMA (Glu-NH-CO-NH-Lys-(Ahx)-[ 68 Ga- N,N '-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine- N,N '-diacetic acid]) has shown promising results in retrospective trials. Our aim was to prospectively compare the detection rates of 68 Ga-PSMA versus 18 F-fluoromethylcholine PET/CT in men who were initially managed with radical prostatectomy, radiation treatment, or both and were being considered for targeted therapy. Methods: A sample of men with a rising PSA level after treatment, eligible for targeted treatment, was prospectively included. Patients on systemic treatment were excluded. 68 Ga-PSMA, 18 F-fluoromethylcholine PET/CT, and diagnostic CT were performed sequentially on all patients between January and April 2015, and the images were assessed by masked, experienced interpreters. The findings and their impact on management were documented, together with the results of histologic follow-up when feasible. Results: In total, 38 patients were enrolled. Of these, 34 (89%) had undergone radical prostatectomy and 4 (11%) had undergone radiation treatment. Twelve (32%) had undergone salvage radiation treatment after primary radical prostatectomy. The mean PSA level was 1.74 ± 2.54 ng/mL. The scan results were positive in 26 patients (68%) and negative with both tracers in 12 patients (32%). Of the 26 positive scans, 14 (54%) were positive with 68 Ga-PSMA alone, 11 (42%) with both 18 F-fluoromethylcholine and 68 Ga-PSMA, and only 1 (4%) with 18 F-fluoromethylcholine alone. When PSA was below 0.5 ng/mL, the detection rate was 50% for 68 Ga-PSMA versus 12.5% for 18 F-fluoromethylcholine. When PSA was 0.5–2.0 ng/mL, the detection rate was 69% for 68 Ga-PSMA versus 31% for 18 F-fluoromethylcholine, and when PSA was above 2.0, the detection rate was 86% for 68 Ga-PSMA versus 57% for 18 F-fluoromethylcholine. On lesion-based analysis, 68 Ga-PSMA detected more lesions than 18 F-fluoromethylcholine (59 vs. 29, P 〈 0.001). The tumor-to-background ratio in positive scans was higher for 68 Ga-PSMA than for 18 F-fluoromethylcholine (28.6 for 68 Ga-PSMA vs. 9.4 for 18 F-fluoromethylcholine, P 〈 0.001). There was a 63% (24/38 patients) management impact, with 54% (13/24 patients) being due to 68 Ga-PSMA imaging alone. Histologic follow-up was available for 9 of 38 patients (24%), and 9 of 9 68 Ga-PSMA–positive lesions were consistent with prostate cancer ( 68 Ga-PSMA was true-positive). The lesion positive on 18 F-fluoromethylcholine imaging and negative on 68 Ga-PSMA imaging was shown at biopsy to be a false-positive 18 F-fluoromethylcholine finding ( 68 Ga-PSMA was true-negative). Conclusion: In patients with biochemical failure and a low PSA level, 68 Ga-PSMA demonstrated a significantly higher detection rate than 18 F-fluoromethylcholine and a high overall impact on management.