The chicken's major histocompatibility complex (MHC) haplotype has profound influence on the resistance or susceptibility to certain pathogens. For example, the B21 MHC haplotype confers resistance to Marek's disease (MD). However, non-MHC genes are also important in disease resistance. For example, lines 6 and 7 both express the B2 MHC haplotype, but differ in non-MHC genes. Line 6, but not line 7, is highly resistant to tumors induced by the Marek's disease herpesviruses and avian leukosis retroviruses. Recently, survival in the field by Thai indigenous chickens to H5N1 high-pathogenicity avian influenza (HPAI) outbreaks was attributed to the B21 MHC haplotype, whereas the B13 MHC haplotype was associated with high mortality in the field. To determine the influence of the MHC haplotype on HPAI resistance, a series of MHC congenic white leghorn chicken lines (B2, B12, B13, B19, and B21) and lines with different background genes but with the same B2 MHC haplotype (Line 6₃ and 7₁) were intranasally challenged with low dose (10 mean chicken lethal doses) of reverse-genetics–derived rg-A/chicken/Indonesia/7/2003 (H5N1) HPAI virus. None of the lines were completely resistant to lethal effects of the challenge, as evidenced by mortality rates ranging from 40% to 100%. The B21 line had mortality of 40% and 70%, and the B13 line had mortality of 60% and 100% in two separate trials. In addition, the mean death times varied greatly between groups, ranging from 3.7 to 6.9 days, suggesting differences in pathogenesis. The data show that the MHC has some influence on resistance to AI, but less than previously proposed, and non-MHC background genes may have a bigger influence on resistance than the MHC.