BACKGROUND:The authors investigated the clinical implication of plasma Epstein‐Barr virus (EBV) DNA assay and 18F‐fluoro‐2‐deoxy‐D‐glucose (18F‐FDG) positron emission tomography (PET) in the detection of recurrent nasopharyngeal carcinoma (NPC).METHODS:Two hundred forty‐five patients with NPC who had previously received treatment and were in a state of remission were monitored prospectively using a plasma EBV DNA assay every 3 to 6 months. 18F‐FDG PET studies were obtained when abnormal EBV DNA or clinically suggestive signs of recurrence were noted.RESULTS:Thirty‐six of 245 patients (14.7%) patients had abnormal EBV DNA tests and underwent PET scans. In the remaining 209 patients, 3658 blood tests were negative. PET scans also were obtained in 5 patients who had undetectable EBV DNA levels but signs that were clinically suggestive of disease recurrence. Subsequent analyses focused on 41 patients who had PET studies. In lesion‐based analyses, the sensitivity, specificity, and accuracy of PET by visual interpretation were 81.8%, 77.1%, and 79.2%, respectively, for all 125 lesions. In patient‐based analyses, the accuracy of PET by visual interpretation was 51.2%. All 36 patients who had detectable plasma levels of EBV DNA had demonstrable NPC recurrences, whereas no recurrences were noted in 5 patients who had undetectable EBV DNA levels but signs that clinically mimicked a recurrence. Compared with annual PET, the annual cost of blood tests every 3 to 6 months per patient saved approximately 77% ∼ 88% in expenses.CONCLUSIONS:The plasma EBV DNA assay correctly predicted all NPC recurrences, and PET had high capacity to localize potential lesion sites. The authors concluded that applying the strategy of EBV DNA screening followed by PET scanning may guide appropriate further treatment planning in a cost‐effective manner. Cancer 2011;. © 2011 American Cancer Society.