Stromal keratitis resulting from ocular infection with herpes simplex virus is a common cause of blindness. This report investigates the role of neovascularization in the pathogenesis of stromal keratitis by measuring the outcome of treatment with the potent anti-angiogenesis cytokine endothelial monocyte-activating polypeptide II (EMAP II). We show that systemic and topical administration of EMAP II from the outset of infection resulted in markedly diminished levels of herpes simplex virus-induced angiogenesis and significantly reduced the severity of stromal keratitis lesions. EMAP II treatment had no demonstrable pro-inflammatory or toxic effects and failed to express antiviral activity. The mechanism of action of EMAP II was shown to proceed by causing apoptosis in vascular endothelial cells. Our data document for the first time the essential role of angiogenesis in the pathogenesis of stromal keratitis and also indicate that the therapy of herpetic stromal keratitis could benefit by procedures that diminish angiogenesis.