Chronic graft-vs-host disease (cGVHD) is an increasingly frequent complication of allogeneic stem cell transplantation. Phenotypically, cGVHD differs from patient to patient; in particular, a subset of patients develops extensive cutaneous fibrosis. Similarly, graft-vs-host disease (GVHD) is distinct in inbred murine donor: recipient pairings, indicating a genetic component to disease phenotype. The B10. D2→ BALB/c (H-2 d) strain pairing uniquely recapitulates key pathologic features of fibrotic human cutaneous cGVHD. To distinguish whether this genetic component is due to differences in genes that modulate immune responses or to the specific Ags targeted, we asked whether skin-dominant cGVHD also develops in the B10→ BALB. B (H-2 b) and B10. BR→ BALB. K (H-2 k) MHC-congenic pairings. Because each MHC haplotype presents different peptides and selects different T cell repertoires, GVHD in each donor: recipient pair undoubtedly targets different Ags. We found that, in contrast to BALB/c recipients, BALB. B mice never manifested skin disease while BALB. K mice developed a modified form of skin disease. Instead, BALB. B and BALB. K recipients developed systemic GVHD which was absent in BALB/c mice. Moreover, in (B10× B10. D2) F 1→(BALB. B× BALB/c) F 1 H-2 b/d transplants, recipients developed both cutaneous and systemic disease. Thus, the selection of immunodominant Ags determines the target and character of GVHD, providing insight into the genetic basis for different forms of GVHD.