Idiopathic retroperitoneal fibrosis (IRF) is a rare human disease characterized by non-neoplastic fibroblastic proliferation associated with chronic inflammatory cells; its pathogenesis is obscure. We undertook an immunohistochemical study for the expression of HLA-DR antigens and other immune-related markers by retroperitoneal proliferating fibroblasts and inflammatory cells from 2 IRF patients. Patterns of immunoreactivity were compared with those expressed by human nodular fasciitis (NF) and granulation tissue. In IRF, most fibroblasts immunostained strongly for HLA-DR antigens, whereas fibroblasts in NF and granulation tissue did, not immunostain at all. The fibroblasts did not immunostain for interleukin 2 receptor, C3b receptor, CD-4, CD-8, or Leu-M1 in any of the tissue studied. Most macrophages and lymphocytes in IRF and NF immunostained Strangly for HLA-DR antigens. In IRF, the CD-4 and CD-8 immunostained T-lymphocytes appeared equally distributed. The expression of HLA-DR antigens by fibroblasts in IRF indicates that this rare disease may indeed be an immune-associated hypersensitivity disorder.