Herpetic stromal keratitis (HSK) is a potentially blinding corneal affliction that can accompany herpes simplex virus type 1 (HSV-1) infections. The disease course in HSK begins with a primary infection by HSV-1, typically mucosal surfaces of the mouth or eye. The virus replicates at the site of infection and proceeds via retrograde axonal transport in sensory neurons to sensory (usually trigeminal) and autonomic ganglia.1 Once inside ganglia, the virus establishes latency, in which the pathogenic virus remains dormant yet the genome persists.2 If these latently infected individuals become immunocompromised (as occurs in elderly or malnourished individuals, or with transplant or HIV-infected patients) or the neurons are exposed to a “triggering” immunosuppressive event, such as stress, trauma, sunlight (UV) irradiation, or fever, the virus is reactivated and rapidly replicates. The virus travels via anterograde axonal transport and returns to the original epithelial surface, where another round of replication occurs.1,2 A multitude of studies have shown that the resulting clinical disease is not associated with this viral replication in the cornea, but rather is due largely to the host immune response being restimulated by the presence of the virus.1–5 As a consequence of these events, active viral replication triggers inflammation and neovascularization of the cornea. Once this inflammation is initiated, the disease continues to progress even though infectious virus can no longer be detected. This inflammation consists of different leukocyte lineages that are recruited to the cornea of patients with HSK, including polymorphonuclear leukocytes (PMNs; neutrophils), macrophages, and T cells, CD4+ and CD8+.1–5 Animal studies have shown that the predominant cell type in diseased corneas is neutrophils.3 Facing a conceivably blinding inflammatory attack, the cornea possesses several means to reduce inflammation and neovascularization. These include the presence of immunosuppressive factors, such as TGF-β,6 IL-1 receptor antagonists, and antiangiogenic factors, such as thrombospondin and pigment epithelium-derived factor (PEDF).7,8 Additionally, the presence of Fas ligand (FasL), which is the focus of this study, often is a critical factor in controlling inflammation and neovascularization, thus reducing disease.9–17 Fas is a member of the tumor necrosis factor-R family, which is a group of type I transmembrane proteins. FasL is a ligand of Fas and is synthesized as a transmembrane molecule that undergoes cleavage and processing through a metalloprotease to become soluble FasL (sFasL). This sFasL contains a “death domain,” which is essential for the induction of apoptosis.18 Studies from our laboratory as well as the laboratories of others have demonstrated that the presence of FasL in the eye is an important barrier to inflammatory cells9–11 and new blood vessels.12–14 In fact, we know that control of inflammation is required for the immune privilege of the eye.9,10 FasL expressed on ocular tissues induces apoptosis in Fas+ lymphoid cells that invade the eye in response to viral infection8 or corneal grafting.11,12 FasL expressed in the retina and the cornea also control new vessel growth beneath the retina and in the cornea by inducing apoptosis of Fas+ vascular endothelial cells.13–15 These studies indicate that the presence of FasL in ocular tissues restricts inflammatory responses. Recently we published that the interaction of Fas with FasL is an important factor in controlling HSK during acute infection of the cornea.17 We demonstrated that mice expressing mutations in Fas (lpr) or FasL (gld) experience significantly worse ocular disease than do wild-type mice, regardless of mouse or viral strain.17 However, as mentioned, acute infection rarely leads to clinical disease in humans. Instead, the reactivated virus is responsible primarily for the symptoms that define corneal keratitis.1–5 Thus, we thought it very important to address the role that Fas and FasL have during recurrent disease when the virus is reactivated from latency. To address the role of Fas-FasL interactions during recurrent HSK, we evaluated this interaction in a mouse model of induced recurrent HSK. We used soluble TNF-related apoptosis inducing ligand (sTRAIL) as our control and standard for comparison, since TRAIL and FasL are members of the TNF family and are known to induce apoptosis in lymphocyte lineages. In this study, we demonstrated that mice treated with sFasL experience a decrease in acute and recurrent models of HSK.