A 75-year-old woman developed periorbital pain and blurred vision OS. Visual acuity (VA) was 20/40 OD, 20/400 OS with mild left relative afferent pupillary defect (APD). Left optic nerve was swollen and hyperemic with peripapillary flame hemorrhages (figure, A). Erythrocyte sedimentation rate (ESR) was 124 mm/h. She was treated with IV methylprednisolone, 250 mg every 6 h. On day 3, headache and vision improved. ESR was 98 mm/h and C-reactive protein was 1.40 mg/L. Rheumatoid factor, antinuclear antibodies, and antineutrophil cytoplasmic antibodies titers were negative. On day 4, left temporal artery biopsy revealed thickened intima and intact internal elastic lamina (figure, B) but no medial necrosis characteristic of giant cell arteritis (GCA). Sections of the temporal artery were deparaffinized and incubated with 10% normal sheep serum (NSS) in phosphate-buffered saline (PBS) for 1 hour at room temperature, rinsed 3 times in PBS, and incubated overnight at 4°C with polyclonal antibodies raised against the varicella-zoster virus (VZV) open reading frame 63 protein (1:1,000 dilution) or with normal rabbit serum (1:1,000 dilution). The next day, sections were washed 3 times in PBS, incubated with a 1:300 dilution of biotinylated goat antirabbit immunoglobulin G (IgG) in PBS containing 5% NSS, washed 3 times in PBS, incubated for 1 hour at room temperature with alkaline phosphatase–conjugated streptavidin (1:100 dilution), and washed 3 times with PBS. The color reaction was developed for 5–30 minutes with fresh fuchsin substrate system. Levamisole was added to the color reaction to block endogenous phosphatase. Uninfected and VZV-infected human fibroblast lung cells were used as controls (not shown). Steroids were changed to oral prednisone 60 mg daily. On day 7, brain MRI with gadolinium was negative. On day 9, pain and vision worsened. On day 11, orbital CT and head CT angiography were negative. On day 15, VA was 20/400 OS with relative left APD. On day 17, OS became blind without direct pupillary light reaction; fundus was obscured by vitreous hemorrhage. CSF contained 8 leukocytes/mm3, protein 72 mg/L, and glucose 54 mg/L. CSF cultures for bacteria, fungi, acid-fast bacilli, and cytology were negative. Because asymptomatic temporal artery biopsy was GCA-negative, VZV ischemic optic neuropathy (ION) was considered, and she was treated with IV acyclovir, 10 mg/kg every 8 hours for 7 days. On day 31, CSF contained anti-VZV IgG but not anti-herpes simplex virus IgG antibody, and serum-to-CSF ratio of anti-VZV IgG was reduced (14) compared to ratios for total IgG (121) and albumin (81). Immunohistochemistry and pathology revealed VZV antigen and neutrophils in the original left temporal artery specimen (figure, C). On day 31, she was treated with oral valacyclovir, 1 gram TID for 6 weeks; prednisone was reduced to 20 mg daily and tapered 5 mg/week. Six weeks later, pain resolved, and VA improved to finger counting. Left optic nerve was pale with clear margins and resolution of hemorrhage.