Conventional work-up (CWU) with chest radiography, abdominal ultrasonography, and skeletal scintigraphy has limited value in M staging of nonkeratinizing nasopharyngeal carcinoma (NPC). Our aim was to evaluate whether 18F-FDG PET could replace CWU by comparing their diagnostic efficacies. Methods: Patients with histologically proven nonkeratinizing NPC and no prior treatment were prospectively enrolled. All study participants underwent CWU and 18F-FDG PET for primary M staging. Distant metastasis was considered to be present if there was any reliable evidence identified within 1 y after diagnosis. The comparative diagnostic efficacies of 18F-FDG PET, CWU, and the combination of 18F-FDG PET and CWU (PET+CWU) were evaluated using the areas under the receiver-operating-characteristic (ROC) curves. Results: Sixty-one (20.3%) of 300 eligible patients were found to have distant metastases. On a patient-based analysis, 18F-FDG PET was found to be more effective than CWU (P < 0.001), whereas it was equally effective with PET+CWU (P = 0.130). On region-based analyses, 18F-FDG PET was more effective than skeletal scintigraphy and chest radiography for detecting bone metastases (P < 0.001) and chest metastases (P < 0.001), respectively. 18F-FDG PET and abdominal ultrasound were equally effective for detecting hepatic metastases (P = 0.127). On region-based analyses, the combination of 18F-FDG PET and CWU did not yield any noticeable increase in diagnostic efficacy. Conclusion: 18F-FDG PET can replace CWU in primary M staging of nonkeratinizing NPC.