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In recent years, a new PET compound (anti-3-18F-FACBC or 18F-fluciclovine) was tested for the detection of prostate cancer relapse. Despite very promising results, only preliminary data were available with regard to the comparison to 11C-choline. The aim of this study was to compare the detection rate of 18F-FACBC and 11C-choline in patients presenting a biochemical relapse.Fifty patients radically treated for prostate cancer and presenting with rising prostate-specific antigen (PSA) levels were consecutively and prospectively enrolled. All the patients were out of hormonal therapy and underwent both 11C-choline PET/CT and 18F-fluciclovine PET/CT within 1 week. The results were compared in terms of detection rate on a patient and lesion basis. Furthermore, a more detailed analysis regarding local, lymph node, and bone relapse was performed.On a patient-based analysis, 18F-fluciclovine detection turned out to be significantly superior to 11C-choline (P < 0.000001). This result was also true on lesion, lymph node, bone lesion, and local relapse analysis (P < 0.0001 in all the cases). There was no significant difference in terms of target to background of positive lesions between 11C-choline and 18F-fluciclovine. When the patients were divided into groups with different PSA levels, 18F-fluciclovine had a superior detection rate for low, intermediate, and high PSA levels.In our experimental conditions, 18F-fluciclovine provided a statistically significant better performance in terms of lesion detection rate as compared with 11C-choline. However, more studies are required to evaluate the clinical significance of these results in terms of sensitivity, specificity, and accuracy.