The development of herpes simplex virus (HSV)-induced disciform stromal disease produced by the intrastromal injection of the RE strain of HSV-1 is characterized by concurrent increases in adenosine deaminase (ADA) activity and corneal thickness. ADA activity increased from 8.6 units/cornea in normal corneas to about 14.1 units and 31.1 units in mock-infected controls and HSV-infected corneas respectively by 15 days postinjection. The molecular weight species of ADA in the corneas of HSV-infected rabbits appeared altered relative to that present in corneas which were not infected. A single topical dose with as low as 0.1% 2'-deoxycoformycin (dCF), an ADA inhibitor possessing immunosuppressive activity, was capable of totally inhibiting the corneal ADA activity. Titration of the free dCF in the cornea following a single topical dose of 0.25% dCF indicated that enough dCF remained in the cornea 24 hrs after instillation to totally inhibit all corneal ADA plus 66 units of additional enzyme. These data suggest that ADA may be a suitable target for immunosuppressive therapy during HSV-induced disciform stromal disease.