Active experimental allergic orchitis (EAO) was induced in Lewis/NCr rats by immunization with homologous rat testicular homogenate. Groups of animals were studied sequentially at five day intervals for histopathologic signs of disease. Inflammatory lesions were first observed in the ductus efferentes as early as 5 days following immunization. Immunohistochemical analysis of the testes, rete testis, ductus efferentes and caput, corpus and cauda epididymis of immunized rats on day five revealed that only the ductus efferentes exhibited a significant increase in the number of interstitial cells expressing Ia antigens (MRC OX-6) as well as CD4 (W3/25) positive helper/inducer T lymphocytes, CD8 (MRC OX-8) positive cytotoxic T lymphocytes and/or natural killer cells and macrophages (MRC OX-42). Increased staining for Ia antigens was also associated with both the vascular and ductal epithelial cells whereas cells within the lumen of the ducts were consistently negative for Ia antigen expression. In contrast, there was no detectable increase in the level of expression of rat MHC class I antigens (MRC OX-18) by any of the cells of the ductus efferentes. Similarly, there was no increase in the number of MAR 18.5 and/or MRC OX-12 positive B lymphocytes. By day 15, autoimmune epididymitis was observed in the cauda and corpus epididymis with the caput becoming involved by day 20. In the testes, the first histopathologic changes observed were scattered inflammatory infiltrates on day 15 and scattered foci of aspermatogenesis on day 20. Inflammatory lesions were first seen in the rete testis and the seminiferous tubules on day 25-30 with maximal involvement occurring on day 35-40. Early inflammatory lesions in the seminiferous tubules were characterized by peritubular and/or interstitial mixed cellular infiltrates. Later lesions included granuloma formation and necrosis. Autoimmune vasitis was not seen in any of the animals studied. Control rats immunized with rat liver homogenate plus adjuvants or adjuvants alone did not exhibit any of the histopathologic lesions described above. The observed results, when compared to those of previous studies examining the sequential histo- and immunopathology of active EAO in the guinea pig and mouse, support the concept that: 1) significant species specificity may exist with regard to regional differences in susceptibility to autoimmune attack within the male reproductive tract and 2) that such differences correlate with early maximal expression of Ia by cells within the male reproductive tract.