The immunosuppressive effects of cyclosporine A (CyA) on the clinical and antiviral immune responses were examined in experimental herpes simplex virus (HSV) keratitis in the rabbit in order to clarify the role that immune lymphocytes play in herpetic stromal disease. Cyclosporine A was administered intramuscularly to rabbits daily starting from the time of corneal infection with HSV until day 14 postinfection. Control HSV-infected rabbits received daily injections of the solvent vehicle alone. HSV-infected rabbits receiving CyA treatment showed more severe and persistent stromal keratitis, and a greater incidence and duration of virus recovery from the cornea. Suppression of cellular immune responses to T cell mitogens, B cell mitogens (anti-rabbit immunoglobulins), and HSV antigens were observed in the CyA treatment group. These results show that in CyA-treated HSV-infected rabbits the antiviral immune responses are inhibited. Acute viral infections with cytopathic viruses such as HSV may therefore be more dramatic, suggesting that CyA may facilitate the potentiation of HSV infections ordinarily suppressed by immune cells.