The recent availability of the genomic sequence spanning the central and telomeric end of the major histocompatibility complex (MHC) has allowed a detailed study of its organisation, gene content and level of nucleotide variability. Previous analyses of nucleotide variability in the MHC have focused on the coding regions of the human leukocyte antigen (HLA) Class I and II genes. Non-coding nucleotide variability has been considered a by-product of exonic diversity. However, with the advent of genomic sequencing, the extent of non-coding nucleotide variability within the MHC has just begun to be appreciated. In this study, we compared different human haplotypes in 370 kb of sequence in the central region of the MHC to show the following:1. unusually high levels of non-coding nucleotide variability, up to 80 times greater than elsewhere in the genome;2. non-coding nucleotide variability greater than 1% at nucleotide sites distant to the Class I genes;3. nucleotide variability greater than 1% maintained over regions containing highly linked loci; and4. distinct troughs and peaks in the level of nucleotide variability.We will discuss these observations in relation to a possible role of nucleotide variability in the organisation of the MHC. (C) 1999 Elsevier Science B.V. All rights reserved.