A 74-year-old woman presented to our hospital for a nonresolving right corneal ulcer in June 2021. She had been previously treated with antibiotics (moxifloxacin), 1% atropine eyedrops, and acyclovir (ACV) ointment for 4 days before she came to our hospital. Her past ocular history was a right corneal ulcer treated with moxifloxacin eyedrops in 2014, and she was treated for right eye herpes keratitis with moxifloxacin eyedrops and ACV ointment in 2020. Her medical history included current treatment for RA consisting of prednisolone 2 mg and methotrexate 2 mg. She did not use contact lenses. She also denied previous ocular trauma and medical or environmental allergies. Her family history was negative. The best-corrected visual acuity in her right eye since childhood was 20/200 because of anisometropia. At presentation, the patient’s main complaint was pain, redness, irritation, and photophobia. She denied general complaints such as an autoinflammatory condition, consistent with periodic fever, aphthosis stomatitis, pharyngitis, adenitis (PFAPA) syndrome over the past 12 months. Corneal sensation was intact. No preauricular or submandibular lymphadenopathy was present. She had a best corrected visual acuity of 20/250 in the right eye and 20/17 in the left eye. Slit-lamp examination showed a corneal epithelial defect and distinct inferior interstitial keratitis with neovascularization affecting the deeper layers of the stroma and extending directly from the limbus without keratic precipitates. The internal growth of the blood vessel reached about 3 mm anterior to the corneal limbus with active pannus extending from 5 o’clock to 6 o’clock. Anterior segment optical coherence tomography (DRT OCT Triton Plus, TOPCON, Tokyo, Japan) showed an irregular surface luminance of the stromal border, unusual reflectivity of the stroma, and swelling towards the corneal endothelium, but the corneal endothelium was intact. No signs of anterior uveitis were noted, and the laser flare meter (FM-600, KOWA Co., Ltd., Aichi, Japan) showed a value of 19.3 ± 1.4. No abnormalities were detected in the posterior segment. The corneal lesions were cultured for bacteria, including Chlamydia, and viruses concomitantly. The DNA of the right scratched corneal sample and of the right aqueous humour were each separately extracted using a DNA Mini kit (Qiagen, Valencia, CA). The DNA was then processed for multiplex solid-phase strip PCR testing targeting 24 specific genomic sequences of human herpesviruses and other pathogens, e.g., herpes simplex virus (HSV) 1, HSV2, varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpes virus (HHV) 6, HHV7, HHV8, adenovirus, human T-cell lymphotropic virus (HTLV)-1, Treponema pallidum, Mycobacterium tuberculosis, bacterial 16S ribosomal RNA (rRNA), Propionibacterium acnes (P. acnes), C. glabrata, Candida species (Candida sp.), Aspergillus, C. krusei, fungal 28S rRNA, Fusarium, Toxocara, Toxoplasma (T. gondii), Acanthamoeba and Chlamydia trachomatis (C. trachomatis) [–]. Real-time PCR for the positive pathogens in multiplex solid-phase strip PCR was also performed. Multiplex solid-phase strip PCR and real-time PCR were performed using a LightCycler 480 II instrument (Roche, Basel, Switzerland). The primers, probes, and PCR conditions used for the above pathogens have been described previously [–]. The results showed that only EBV-DNA was detected with a load of 6.86 × 10E-1 copies/μg in the corneal sample, both PCR-exams (multiplex solid-state PCR and real-time PCR) were positive and we were able to exclude the other 23 pathogens, such as HSV1 and Acanthamoeba. Extensive testing was conducted to rule out infectious and autoimmune causes of interstitial keratitis (serum IgM and IgG for EBV, TPA and ACE; X-ray of the mediastinum and chest). Only EBV serology was found to be positive, displaying a panel compatible without IM (VCA IgM negative, VCA IgA negative, VCA IgG 1:160, EB-nuclear antigen (EBNA) negative). The patient was started on topical antibiotics (tobramycin, cefmenoxime, and moxifloxacin eye drops) after discontinuing topical treatment, including ACV ointment, prescribed by a previous doctor. After confirming that bacterial culture was negative and EBV-DNA was detected in the corneal stroma sample, we started her on topical steroid eye drops. The clinical picture at 1 week of treatment showed better resolution, epithelial staining was reduced, and the inferior pannus showed significant resolution, with regression of the vessels. Two weeks later, the patient’s symptoms improved. The vessels had remarkably reduced and the only corneal haze was in the area of the previous vascular pannus. She showed no PFAPA (periodic fever, aphthosis stomatitis, pharyngitis, adenitis) syndrome symptoms and no signs of diseases in the left eye during the course. Anterior segment OCT revealed a thick intact epithelium, hyporeflectivity, and decreasing thickness of the stroma.