Electron microscopic observations of testes of sterile, backcross T/tw18 mice which spontaneously develop allergic orchitis have demonstrated accumulations of lymphocytes and occasional plasma cells between seminiferous tubules in affected mice. Many lymphocytes appeared to be insinuated amongst cytoplasmic processes of the peritubular adventitial cells which, in most samples, provided a barrier to direct infiltration of the germinal epithelium by lymphocytes. Although lymphocytes were rarely observed within the seminiferous epithelium, extensive degeneration of spermatogenic cells was observed within affected tubules. Sertoli cells phagocytosed degenerating germ cells at all stages of differentiation. In-vitro co-cultivation of syngeneic T/tw18 spleen and testicular cells revealed that testicular cells from sterile T/tw18 mice failed to activate suppressor T lymphocytes; consequently, the syngeneic splenocytes displayed a vigorous proliferative response to testicular autoantigens. Testicular cells from younger, fertile T/tw18 males, on the other hand, behaved like testicular cells from normal mice, triggering suppressor T cell activity and, thereby, abrogating proliferation of splenocytes. These results suggest genetic factors, introduced in the course of inbreeding and associated with chromosome 17, are responsible for the failure of spermatogenic cells from sterile T/tw18 males to maintain normal tolerance to their own antigens in vivo; allergic orchitis is an extreme manifestation of the inability of the defective germ cells to initiate normal T lymphocyte mediated suppression of an immune response.