Congenital heart block develops in fetuses of anti-Ro52 Ab-positive women. A recurrence rate of 20%, despite the persistence of maternal autoantibodies, indicates that there are additional, yet unidentified, factors critical for development of congenital heart block. In this study, we demonstrate that besides the maternal MHC controlling Ab specificity, fetal MHC-encoded genes influence fetal susceptibility to congenital heart block. Using MHC congenic rat strains, we show that heart block develops in rat pups of three strains carrying MHC haplotype RT1 av1 (DA, PVG.AV1, and LEW.AV1) after maternal Ro52 immunization, but not in LEW rats (RT1 l ). Different anti-Ro52 Ab fine specificities were generated in RT1 av1 versus RT1 l animals. Maternal and fetal influence was determined in an F 2 cross between LEW.AV1 and LEW strains, which revealed higher susceptibility in RT1 l than RT1 av1 pups once pathogenic Ro52 Abs were present. This was further confirmed in that RT1 l pups more frequently developed heart block than RT1 av1 pups after passive transfer of RT1 av1 anti-Ro52 sera. Our findings show that generation of pathogenic Ro52 Abs is restricted by maternal MHC, whereas the fetal MHC locus regulates susceptibility and determines the fetal disease outcome in anti-Ro52–positive pregnancies. Ro52 immunization-induced animal model of congenital heart block to study the role of different MHC (RT1) and non-MHC genes in susceptibility to the heart block in various rat strains. Our data demonstrate that production of Ro52 Abs with pathogenic specificity is restricted by maternal MHC, whereas a different set of MHC-encoded genes in the fetus confers increased susceptibility to congenital heart block and determines the disease outcome in Ro52-positive pregnancies. thermocycling of 72˚Cfor1.5min,followed by a final extension at 72˚C for 7 PCR products were size frac-tionated on 6% polyacrylamide gels and visualized by autoradiography. All genotypes by two independent observers.