A study of the human leukocyte antigen (HLA) genetic characteristics in the Zhuang, the largest ethnic population in China, would provide insight into Zhuang history and give a useful tool for disease associations, transplantation, and anthropology. In the present study, we report the comprehensive HLA-A, HLA-B, HLA-C, and HLA-DRB1 alleles and haplotypes in the Zhuang population of southern China for the first time. A total of 13 HLA-A, 24 HLA-B, 22 HLA-C, and 18 HLA-DRB1 were identified in 104 Zhuang individuals. The frequencies of HLA-A*11:01, A^*02:07, A^*24:02, A^*02:03, and A^*33:03 on A loci, B^*15:02, B^*58:01, B^*46:01, and B^*13:01 on B loci, C^*03:04, C^*08:01, C^*01:02, C^*03:02, and C^*07:02 on C loci, and DRBl*15:01, DRBl^*16:02, DRB1^*14:01, DRBl^*15:02, and DRBI^*03:01 on the DRB1 loci were 〉10%. The A^*33:03-C^*03:02-B^*58:01-DRBl^*03:01 and A^*02:07-C^*01:02- B^*46:01-DRB1^*14:01 haplotypes were predominant in the Zhuang. The phylogenetic tree, as well as the analysis of haplotypes, suggested that the Zhuang are genetically similar to southern Chinese populations, especially the Zhuang-Dong language-speaking populations, such as the Bouyei, Dai, and Maonan. Even though the Zhuang and southern Chinese populations shared common alleles and haplotypes, the Zhuang has maintained its unique genetic characteristics.