The influence of genes of the major histocompatibility complex (MHC) class II and class III loci on typhoid fever susceptibility was investigated. Individuals with blood culture— confirmed typhoid fever and control subjects from 2 distinct geographic locations in southern Vietnam were genotyped for HLA-DRB1 and HLA-DQB1 alleles, the gene that encodes tumor necrosis factor (TNF)—α (TNFA [−238] and TNFA [−308]), the gene that encodes lymphotoxin-α, and alleles of the TNF-α microsatellite. HLA-DRB1*0301/6/8, HLA-DQB1*0201-3, and TNFA*2 (−308) were associated with susceptibility to typhoid fever, whereas HLA-DRB1*04, HLA-DQB1*0401/2, and TNFA*1 (−308) were associated with disease resistance. The frequency of all possible haplotypes of the 3 individually associated loci were estimated and were found to be significantly different in typhoid case patients and control subjects (χ² = 55.56, 32 df; P = .006). Haplotypes that were either protective (TNFA*1 [−308].DRB1*04) or predisposed individuals to typhoid fever (TNFA*2 [−308].DRB1*0301) were determined. This report identifies a genetic association in humans between typhoid fever and MHC class II and III genes.