Purpose To assess the accuracy of staging positron emission tomography (PET)/computed tomography (CT) in detecting distant metastasis in patients with local-regionally advanced cervical and high-risk endometrial cancer in the clinical trial by the American College of Radiology Imaging Network (ACRIN) and the Gynecology Oncology Group (GOG) (ACRIN 6671/GOG 0233) and to compare central and institutional reader performance. Materials and Methods In this prospective multicenter trial, PET/CT and clinical data were reviewed for patients enrolled in ACRIN 6671/GOG 0233. Two central readers, blinded to site read and reference standard, reviewed PET/CT images for distant metastasis. Central review was then compared with institutional point-of-care interpretation. Reference standard was pathologic and imaging follow-up. Test performance for central and site reviews of PET/CT images was calculated and receiver operating characteristic analysis was performed. Generalized estimating equations and nonparametric bootstrap procedure for clustered data were used to assess statistical significance. Results There were 153 patients with cervical cancer and 203 patients with endometrial cancer enrolled at 28 sites. Overall prevalence of distant metastasis was 13.7% (21 of 153) for cervical cancer and 11.8% (24 of 203) for endometrial cancer. Central reader PET/CT interpretation demonstrated sensitivity, specificity, positive predictive value (PPV), and negative predictive value of 54.8%, 97.7%, 79.3%, and 93.1% for cervical cancer metastasis versus 64.6%, 98.6%, 86.1%, and 95.4% for endometrial cancer, respectively. By comparison, local institutional review demonstrated sensitivity, specificity, PPV, and negative predictive value of 47.6%, 93.9%, 55.6%, and 91.9% for cervical cancer metastasis and 66.7%, 93.9%, 59.3%, and 95.5% for endometrial cancer, respectively. For central readers, the specificity and PPV of PET/CT detection of cervical and endometrial cancer metastases were all significantly higher compared with that of local institutional review (P < .05). Central reader area under the receiver operating characteristic curve (AUC) values were 0.78 and 0.89 for cervical and endometrial cancer, respectively; these were not significantly different from local institutional AUC values (0.75 and 0.84, respectively; P > .05 for both). Conclusion FDG PET/CT demonstrates high specificity and PPV for detecting distant metastasis in cervical and endometrial cancer and should be included in the staging evaluation. Blinded central review of imaging provides improved specificity and PPV for the detection of metastases and should be considered for future oncologic imaging clinical trials. RSNA, 2017.