This article describes the histopathology, immunohistochemistry, and varicella zoster virus DNA in situ hybridization of 14 corneal buttons obtained from 14 patients (average age 69.0 years) after perforating keratoplasty (four patients) or surgical enucleation (10 patients) at different times after the clinical onset of herpes zoster ophthalmicus (average 58.7 months). The main histopathologic features were intense stromal vascular scarring (12 patients) and granulomatous reaction to Descemet's membrane (nine patients). Using the peroxidase-antiperoxidase method, varicella zoster virus (VZV) antigen could be detected by immunohistochemistry in two patients within epithelial cells of the cornea and in the limbal episclera during the active phase of herpes zoster ophthalmicus. For in situ hybridization we used the 35Slabeled HindIll A and C fragment of VZV and identified viral DNA in five corneal buttons obtained 1 day to 8 years after the clinical onset of infection. Viral DNA was mainly found in mononuclear cells with eosinophilic intracytoplasmic inclusions within vascular stromal scars, in keratocytes, and in epithelial cells of the cornea. Our results show that VZV DNA is detectable in human cornea even 8 years after the clinical onset of herpes zoster ophthalmicus and may indicate VZV persistence in a latent form in corneal tissue or reactivation of the virus from an endogenous or exogenous source causing a severe and often recurrent keratitis in the progress of herpes zoster ophthalmicus.