A comparison is made between immunologically induced and non-immunologically induced granulomas in guinea-pigs injected with metals (zirconium and aluminum) or with mycobacteria (BCG vaccine and Mycobacterium leprae). Immunological granulomas were characterized by epithelioid cells and fibrosis, whereas non-immunological granulomas contained phagocytosing macrophages with little evidence of fibroblast activation. Epithelioid cells carry the same specific macrophage antigen as phagocytosing macrophages and this can be detected by the use of a specific monoclonal antibody. However, they differ from phagocytosing macrophages in that they are poorly phagocytic, not glass adherent and lack Ia antigen. They are however secretory cells with rough endoplasmic reticulum. A relation between the presence of these cells and increased collagen synthesis is indicated. A study of accessory cell function showed that the epithelioid cells of BCG granulomas were able to support mitogen-induced but not antigen-induced proliferation of T lymphocytes. The macrophages of M. leprae granulomas did not support either a mitogen- or antigen-induced proliferative response.