Epstein–Barr virus (EBV) infects more than 95% of adults worldwide but is associated with endemic nasopharyngeal carcinoma (NPC) specifically in southern China1–4. Here, through a stepwise host–EBV genome interaction analysis, we identify a genetic interaction between HLA-A*11:01 and the high-risk EBV variant 85841G as a key determinant of NPC risk. Individuals carrying a susceptible HLA-A background (HLA-A*11:01− or HLA-A*02:07+) and infected with the high-risk 85841G EBV form a dual-risk subgroup with substantially elevated, interaction-driven NPC risk, far exceeding the effects of host or virus alone. This dual-risk subgroup comprises 20.5% of the population and accounts for approximately 47% of NPC cases. We show that EBV 85841G encodes an EBNA3B peptide that binds to HLA-A*11:01 and elicits specific T cell responses capable of lysing EBV+ B cells transformed by 85841G-carrying strains, and is associated with reduced salivary viral load and lower NPC risk among A*11:01 carriers. Evolutionary analysis reveals that 85841G arose via ancient recombination events between northern and southern EBV and subsequently underwent clonal expansion in southern China, leading to co-enrichment of interacting host and viral risk factors that, in turn, contribute to NPC endemicity. These findings reveal a markedly stratified, interaction-driven risk architecture in NPC and highlight opportunities for precision prevention.
