We investigated the prognostic implication of pretreatment plasma/serum EBV DNA concentration, as measured by real-time quantitative PCR, in nasopharyngeal carcinoma (NPC). In 91 prospectively recruited NPC patients, those with recurrence or metastasis within the first year after treatment had a higher median plasma EBV DNA concentration than those without events (41,756 copies/ml versus 5,807 copies/ml; P < 0.001, Mann-Whitney rank-sum test). In multivariate logistic regression analysis, plasma EBV DNA was an independent prognostic indicator for early clinical events [relative risk = 3.8 (95% confidence interval, 1.6-9.2 for each 10-fold increase in plasma EBV DNA concentration; P = 0.003)]. In a second cohort of 139 NPC patients followed-up for a median period of 2,027 days (interquartile range, 597-2,335 days), serum EBV DNA was found to be a significant variable associated with NPC-related death in multivariate Cox's regression analysis [relative risk = 1.6 (95% confidence interval, 1.1-2.1 for each 10-fold increase in serum EBV DNA concentration; P = 0.007)]. The quantitation of circulating EBV DNA may thus allow improved prognostication of NPC.