Technical Abstract: The chicken’s major histocompatibility complex (MHC) haplotype has profound influence on the resistance or susceptibility to certain pathogens such as B21 MHC haplotype confers resistance to Marek’s disease (MD). However, non-MHC genes are also important in disease resistance. For example, both 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 B21 MHC haplotype while 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 H5N1 HPAI virus rgA/chicken/Indonesia/7/2003. None of the lines were completely resistant to lethal effects of the challenge as evident 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 2 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 the resistance to AI, but less than previously proposed, and non-MHC background genes may have a bigger influence on resistance than the MHC.