Epstein-Barr virus (EBV) and human leukocyte antigen (HLA) polymorphisms have shown the most prominent associations with the risk of nasopharyngeal carcinoma (NPC), a cancer that is endemic in southern China. Despite a priori biological knowledge that HLA genes are essential for the host immune response against viruses, the interplay between HLA genetics and EBV in the etiology of NPC is largely unknown. Using a population-based case-control study in NPC-endemic southern China, we apply a causal inference framework to disentangle interaction and mediation effects between two host HLA SNPs rs2860580 and rs2894207 and EBV variant 163364. We discover the strong interaction effects between the high-risk EBV subtype and both host SNPs on NPC risk within the original dataset and replicate the discovery of the significant interaction effects in an independent dataset (for rs2860580, relative excess risk due to interaction with EBV (RERI) = 4.08, 95% confidence interval (CI) = 2.03-6.14; for rs2894207, RERI = 3.37, 95% CI = 1.59-5.15). Interaction with the high-risk EBV accounts for the majority of the genetic effects of both host HLA SNPs on NPC risk. The effects of rs2860580 and rs2894207 on NPC risk mediated through increasing the frequency of the high-risk EBV are weak. These results indicate that host HLA genes and the high-risk EBV have a joint effect on NPC risk. Our study highlights that prevention strategies targeting the high-risk EBV subtype may largely reduce NPC risk associated with both EBV and host genetic susceptibility.