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In our study, 1,105 cases of nasopharyngeal carcinoma (NPC) and 1,430 normal controls recruited from Hunan province, southern China were typed for human leukocyte antigen (HLA)‐B locus by Sanger sequencing exons 2–4. Besides confirming the NPC association with HLA‐B*46:01 allele, HLA‐A*02:07‐B*46:01 and HLA‐A*33:03‐B*58:01 haplotypes (all positive), and HLA‐B*13 lineage (negative), all of which were relatively common, strong negative associations were observed for five low‐frequency and rare alleles or lineages, including HLA‐B*07, ‐B*27:04, ‐B*39, ‐B*51:02 and ‐B*55:02, with odds ratio (OR) ranging from 0.16 to 0.3 (all pcorrected < 0.05). These strong protective associations were independent of linkage disequilibrium (LD) between HLA‐A and HLA‐B loci. Further analysis indicated a single amino acid change from histidine to tyrosine at residue 171 is probably crucial for the mutant allele, HLA‐B*51:02, to mediate resistance to NPC. A subset of NPC cases (n = 821) and normal controls (n = 1,035) were tested for antivirus capsid antigen immunoglobulin A (anti‐VCA IgA), which differed drastically between the two groups [67.7% vs. 5.5%, OR (95% confidence interval) = 36 (26.55–48.81), p < 0.0001]. HLA‐B allelic variation did not associate with seropositivity for anti‐VCA IgA in either group. Results from our study show, more clearly than previously, the existence of a cluster of low‐frequency and rare HLA‐B variants conferring low, or very low risk to NPC, a phenomenon not observed in other ethnic groups. Our data shed new insights into genetic susceptibility to NPC in southern Chinese populations. Future independent studies are warranted to replicate the findings reported in our study. What's new? Southern Chinese populations have uniquely high rates of nasopharyngeal cancer (NPC). Low‐frequency and rare HLA variants implicated in genetic predisposition to NPC remain to be fully identified. Here, the authors compared a large cohort of NPC patients and controls from southern China. They sequenced the HLA‐B locus in approximately 2,500 individuals looking for an association with NPC risk. Five low‐frequency HLA‐B allelic variants correlated with strong protection against the disease. These variants may help mount a T cell response against Epstein‐Barr virus. The researchers identified a single nucleotide change that they suspect may confer the protective effect. [ABSTRACT FROM AUTHOR]