During a previous investigation an association was found between major histocompatibility complex (MHC)-DRB1 alleles and faecal egg counts following natural infection predominantly involving Ostertagia circumcincta in a flock of Scottish Blackface sheep. To localise the disease-resistance locus we screened the same flock for an MHC class I microsatellite and a newly developed microsatellite for the DY locus located in the class IIb subregion. Some alleles at both additional loci were associated with resistance to infection. Least-squares analysis of variance indicated that in 6-month-old lambs, substitution of the most common alleles by the alleles associated with resistance would result in an 8- and a 218-fold reduction in faecal egg counts for MHC class I and DY, respectively. These results indicate that genes within the MHC genes play a large and significant role in the development of resistance to a widespread, important and natural parasite.