Recently, human retinal pigment epithelial (RPE) cells have been demonstrated to express class II, HLA-DR, antigens both in vivo and in vitro. HLA-DR antigens were detected on RPE cells from patients with uveitis and retinitis pigmentosa. In addition, in vitro studies revealed that not only does this cell express HLA-DR antigen but also that this antigen can be modulated by the lymphokine, interferon (IFN)-gamma. In this study we evaluated the development of the murine class II, Ia, antigens on RPE cells in experimental autoimmune uveoretinitis (EAU). Ia antigen was evaluated with the avidin-biotin-peroxidase technique. Ia antigen was not detected on RPE cells from normal rats. However, Ia antigen was detected on the surface of RPE cells from EAU rats four days prior to the development of clinical and histopathological EAU. Moreover, the expression of Ia antigen on RPE cells from EAU rats continued to persist until one and one-half months after immunization. This study demonstrates that during the course of EAU the RPE cell is activated to express Ia antigens. This antigen expression may be important in the initiation and/or perpetuation of immune reactivity in the eye.