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PurposeTo estimate the effectiveness of an Epstein–Barr virus (EBV) serology-based screening program to reduce nasopharyngeal carcinoma (NPC) mortality in a cluster randomized controlled trial in an NPC high-risk population.MethodsSixteen towns in Sihui and Zhongshan Cities, China were selected; eight were randomly allocated to the screening group and eight to the control group. Cantonese residents aged 30-69 years with no history of NPC were included January 1, 2008 to December 31, 2015. Residents in the screening towns were invited to undergo serum EBV VCA/EBNA1 IgA antibody tests; others received no intervention. Screening lasted through December 31, 2015; the population was followed through December 31, 2017.ResultsA total of 175,037 residents in the screening group and 184,526 residents in the control group were included. NPC incidence was similar in screening and control groups. A 28% reduction in NPC mortality was observed in the screening versus control arms in the overall study population (8.0 NPC deaths per 1000 person years versus 11.1; adjusted rate ratio [aRR]=0.72; 95% confidence interval=0.48-1.09; p=0.12). A stronger benefit was observed among individuals aged >50 (aRR=0.63; p=0.048) compared to those ConclusionIn this near 10-year trial, serology EBV VCA and EBNA1 IgA antibody testing led to a reduction in NPC mortality, particularly among individuals aged ⩾50. EBV antibody-based screening for NPC is effective at reducing NPC mortality in high-risk populations.Trial registration numberNCT00941538