Purpose <p>To compare the diagnostic values of novel ¹⁸F-AlF-PSMA-11 versus ⁶⁸Ga-PSMA-11 PET/CT has been consolidated as a clinically relevant technique for the evaluation of patients with prostate cancer, whereas 18F-AIF-PSMA-HBED-CC is a novel tracer produced in our center, with suitable radiochemical purity for clinical purposes and it is also cost-effective. The aim was to compare the diagnostic values of novel 18F-AlF-PSMA-11 versus 68Ga-PSMA-11 for the evaluation of prostate cancer patients with biochemical recurrence.</p> Methods <p>37 patients (median age: 67 ± 9.18, range: 53–85 years; median PSA level: 5.0 ± 7.48, range: 0.13–31.2 ng/mL) with biochemical recurrence after radical prostatectomy (76%) or radiotherapy (24%) underwent routine ¹⁸F-AlF-PSMA-11 and ⁶⁸Ga-PSMA-11 64-slice PET/CT scans with time-of-flight correction. We measured the SUVmax in all coincident lesions. Histopathology, imaging, and/or clinical follow-up were considered as reference standard. Sensitivity, specificity, and predictive values were calculated.</p> Results <p>¹⁸F-AlF-PSMA-11 and ⁶⁸Ga-PSMA-11 PET/CT demonstrated abnormal findings in 17 and 18 patients (46% and 49%), respectively. Detection rates for post-prostatectomy patients and for post-radiotherapy patients were 43% and 67% respectively. 76 suspicious lesions were detected by at least one radiopharmaceutical in bone (<i>n</i> = 35), lymph nodes (<i>n</i> = 33) and prostate gland (<i>n</i> = 8). A significant correlation was found between the SUVmax of both radiopharmaceuticals (<i>r</i> = 0.72, <i>P</i> = 0.02). We found a significantly higher SUVmax for ⁶⁸Ga-PSMA-11 compared to ¹⁸F-AlF-PSMA-11 in lymph node and prostate: 8.1 (2.77–25.49) versus 7.7 (2.55–24.78) and 17.3 (5.1-47.12) versus 14.5 (4.69–38.63), median (range), for each tracer, respectively (<i>P</i> &lt; 0.001). ¹⁸F-AlF-PSMA-11 SUVmax was higher in bone foci compared to gallium (8.6 vs. 6.6; <i>P</i> &lt; 0.001). we found a significantly higher LBR for ¹⁸F-AlF-PSMA-11 in concordant bone lesions (<i>P</i> = 0.001) and for ⁶⁸Ga-PSMA-11 in lymph node and prostate concordant lesions (<i>P</i> = 0.015 and 0.041, respectively). Detection rates for disease por PSA levels &lt; 1 and &gt; 1 ng/mL were 33% and 59% respectively. Additionally, detection rates for disease for PSA levels &lt; 1.77 and &gt; 1.77 ng/mL (median PSA of our sample) was 28% and 72%, respectively. Sensitivity, specificity, positive and negative predictive values were 0.50, 0.90, 0.94 and 0.45 for ¹⁸F-AlF-PSMA-11, and 0.63, 0.90, 0.94 and 0.47 for ⁶⁸Ga-PSMA-11, respectively.</p> Conclusions <p>¹⁸F-AlF-PSMA-11 and ⁶⁸Ga-PSMA-11 seems to have similar, complementary and clinically relevant diagnostic values for the detection of prostate cancer lesions in the biochemical recurrence scenario. More studies with a larger number of patients are needed in order to test for the possible complementary clinical value of these PET/CT techniques.</p>