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Background: According to the National Comprehensive Cancer Network Guidelines, 18F-fluciclovine PET/CT is considered appropriate after negative standard of care (SOC) imaging., Objective: To prospectively compare 18F-fluciclovine to SOC imaging, investigate whether it should be done when SOC imaging is (+), and evaluate its detection rate in patients receiving androgen deprivation therapy., Methods: We recruited 57 prostate cancer patients with biochemical recurrence with 18F-fluciclovine PET/CT and SOC imaging within 30 days. Prostate-specific antigen (PSA) level, Gleason score (GS), history of radical prostatectomy (RP), radiation therapy (RT) or hormone therapy (HT) were reviewed., Results: The 57 patients had a median PSA of 2.6 and average GS of 7.4; 27 (47.4%) had RP, 28 (49.1%) had RT, 1 (1.75%) had HT and 1 (1.75%) observation only. 18F-fluciclovine identified disease recurrence in 45/57 patients (78.9%), including oligometastasis in 18/45 (40%). SOC imaging identified recurrent disease in 12/57 patients (21.1%) while 18F-fluciclvoine identified additional sites of disease in 11/12 (91.7%). The (+) 18F-fluciclovine studies had a median PSA 2.6 ng/ml compared to 6.0 ng/ml in the (+) SOC studies., Conclusion: 18F-fluciclovine was superior to SOC imaging for lesion detection, identification of oligometastasis and identification of additional sites of disease., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)