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A genetic system controlling lymphocyte alloantigens of the horse is described. Alloantisera to paternal histocompatibility antigens induced as a result of pregnancy in mares were used in an antibody-mediated complement-dependent microcytotoxicity assay to define 15 Equine Leukocyte Antigen (ELA) specificities using cluster analysis. In this study 369 sera were screened for alloantibody using lymphocytes from 10 randomly selected, unrelated horses. A high proportion (83%) of these sera were found to be positive for antibody to lymphocyte alloantigens. After initial cluster analysis, 120 of the most discriminating sera were tested against a further 400 horses. The phenotypic distribution of the ELA antigens in 304 randomly selected horses and their segregation behavior in a family study of 161 offspring and their sires and dams indicated that 13 of the alloantigens behaved as members of a single allelic series, provisionally named locus ELA-A. These 13 alloantigens accounted for approximately 90% of the genes at this locus. Large differences in the frequencies of some of the ELA-A specificities were found between the Standardbred and Thoroughbred breeds of horses. Rare‘blank’alleles which were predicted by the estimated cumulative gene frequency of known alleles at ELA-A were identified in informative families. The ELA system is probably the Major Histocompatibility Complex of the horse, although the evidence for this is not yet conclusive. The high incidence of sensitization to ELA antigens in pregnant mares suggests that the horse may be an interesting model for investigations of the maternal immunological response to fetal histocompatibility antigens.