We have established a non-human primate model of experimental ocular histoplasmosis. This model has been shown to result in chronic lesions that resemble typical 'histo spots' or choroidal scars but that contain infiltrates of lymphocytes for as long as 10 yr following intracarotid injection of live Histoplasma capsulatum. Using this model, we attempted to reactive these late choroidal lesions via intracarotid challenge with specific antigen (heat-killed H. capsulatum). No clinical changes suggestive of reactivation of these lesions were observed following this antigenic challenge. However, immunopathologic analysis of choroidal lesions at 1, 3 and 7 days after antigenic challenge revealed significant increases in both the numbers of inflammatory cells and the relative percentages of the helper/inducer lymphocyte and macrophage populations. Our results demonstrate that, following antigenic challenge, a cellular change, consistent with a type IV delayed hypersensitivity, can be observed in previously active, but clinically quiescent, histoplasmosis lesions. In light of the many parallels between our primate experimental model and human ocular histoplasmosis, our findings suggest that, in the human, significant immunopathologic activity may occur subclinically in the choroid of affected individuals. It is possible that repeated bouts of subclinical reactivation may induce or enhance chronic choroiditis and, over many years, ultimately produce slow progressive damage to the Bruch's membrane/retinal pigment epithelium complex, resulting in clinically 'active' macular disease and, in selected cases, subretinal neovascularization.