SUMMARY The production and testing of “double congenic” strains of mice are described. BIO. A and B10.D2/o females were mated with B10.129(21M) males, and their Ft offspring were intercrossed. The F2 progeny were selected on the basis of coat color, tumor challenge, skin grafting, and hemagglutination testing for the genotypes H-2a H-4bp/H-2a H-4bp and H-2d lI-4bp//-2d Il-4bp. The resulting strains wore designated B10-//-.T H-4bpWts and B10-//-2* H-4bp/W ts. Skin grafts were transplanted orthotopically from BW-II-2a//-//p and B10-H-2a11-4b p donors to BIO. A and B10.D2/O recipients, respectively. The speed of rejection of grafts incompatible at the H-4 locus (11-4b-11-4°) depended upon the H-2 haplotype. On the H-2d background, grafts were rejected with a mean survival time (MST) of 40.4 days. Grafts were rejected more slowly on H-2h and H-2a backgrounds with MSTs of 48.il days and >S8.1 and >70.4 days (two groups for H-2a), respectively. The utility of double congenic strains in investigating regulation of the immune response to non-H-2 histocompatibility antigens by the H-2- linked immune response region is discussed.