Neuroendocrine tumors (NETs) can be visualized using radiolabeled somatostatin analogs. We have previously shown the clinical potential of 64 Cu-DOTATATE in a small first-in-human feasibility study. The aim of the present study was, in a larger prospective design, to compare on a head-to-head basis the performance of 64 In-diethylenetriaminepentaacetic acid (DTPA)-octreotide ( 111 In-DTPA-OC) as a basis for implementing 64 Cu-DOTATATE as a routine. Methods: We prospectively enrolled 112 patients with pathologically confirmed NETs of gastroenteropancreatic or pulmonary origin. All patients underwent both PET/CT with 64 Cu-DOTATATE and SPECT/CT with 111 In-DTPA-OC within 60 d. PET scans were acquired 1 h after injection of 202 MBq (range, 183-232 MBq) of 64 Cu-DOTATATE after a diagnostic contrast-enhanced CT scan. Patients were followed for 42-60 mo for evaluation of discrepant imaging findings. The McNemar test was used to compare the diagnostic performance. Results: Eightyseven patients were congruently PET-and SPECT-positive. No SPECT-positive cases were PET-negative, whereas 10 false-negative SPECT cases were identified using PET. The diagnostic sensitivity and accuracy of 64 Cu-DOTATATE (97% for both) were significantly better than those of 111 In-DTPA-OC (87% and 88%, respectively, P 5 0.017). In 84 patients (75%), 64 Cu-DOTATATE identified more lesions than 111 In-DTPA-OC and always at least as many. In total, twice as many lesions were detected with 64 Cu-DOTATATE than with 111 In-DTPA-OC. Moreover, in 40 of 112 cases (36%) lesions were detected by 64 Cu-DOTATATE in organs not identified as disease-involved by 111 In-DTPA-OC. Conclusion: With these results, we demonstrate that 64 Cu-DOTATATE is far superior to 111 In-DTPA-OC in diagnostic performance in NET patients. Therefore, we do not hesitate to recommend implementation of 64 Cu-DOTATATE as a replacement for 111 In-DTPA-OC.