Background: This is a prospective single-center, single-arm, head-to-head phase 3 study of paired ¹⁸F-fluciclovine (FACBC) and ⁶⁸Ga-PSMA-11 (PSMA) PET/CT scans for localizing early biochemical recurrence (BCR) of prostate cancer (PCa) after radical prostatectomy (RP) (NCT02940262). Methods: Fifty consecutive patients with BCR and prostate specific antigen (PSA) levels ranging from ≥0.2 to ≤2.0 ng/mL without any prior salvage therapy were included. All patients underwent FACBC and PSMA PET/CT scans within ≤15 days. PET/CT scans were each interpreted by 3 independent blinded expert readers not involved in study design and data acquisition. Region consensus interpretation (T,N,M1a,M1b,M1c) was generated based on majority rule in cases of reader disagreement (2 vs 1). PET/CT scans were considered as positive if any region was rated as positive. Detection rates per-patient and per-region served as primary study endpoint. Results: Median time interval between the 2 scans was 6 days (range 1-15). Median PSA level at the time of imaging was 0.50 ng/ml (mean 0.63; range 0.2-2.0 ng/ml). The detection rates were significantly lower with FACBC than with PSMA PET/CT per-patient (26% vs 56%; p = 0.003) and per-region for pelvic nodes (N) (8% vs 30%; p = 0.003) or any extra-pelvic lesions (M) (0% vs 16%; p = 0.008). Reader agreement for PSMA PET/CT image interpretations was significantly higher than for FACBC PET/CT (0.67 vs 0.20; p = 0.015). Conclusions: In patients with BCR and low serum PSA levels after RP, PSMA PET/CT demonstrates higher detection rates and superior reader agreement when compared with FACBC PET/CT. Therefore, PSMA PET/CT should be the imaging modality of choice in patients with early BCR. Clinical trial information: NCT03515577