<h3>Objective:</h3> To report a case of a 66-year-old woman with a history of aquaporin-4-IgG seropositive (AQP4-IgG+) Neuromyelitis Optica Spectrum Disorder (NMOSD) and concurrent metastatic oral cavity squamous cell carcinoma (SCC) who presented with acute left-sided hemiplegia in the setting of pembrolizumab therapy. <h3>Background:</h3> Pembrolizumab is an immune checkpoint inhibitor (ICI) approved for the treatment of several malignancies. ICIs are known to cause a wide variety of immune-related adverse events. While there have been no studies on the safety of ICIs in NMOSD patients, there was a case reported of newly-diagnosed NMOSD following nivolumab treatment. This is a novel case of an NMOSD attack following pembrolizumab treatment in an AQP4-IgG+ NMOSD patient on long-term anti-CD19 B cell depleting therapy. <h3>Design/Methods:</h3> Case report <h3>Results:</h3> A 66-year-old woman with AQP4-IgG+ NMOSD, diagnosed in 2015 and treated with inebilizumab, was diagnosed with metastatic SCC of the tongue in February 2022. She had received inebilizumab every six months from February 2016 to October 2021; infusion was cancelled in April 2022 due to cytotoxic chemotherapy (CD19+ 2 cells/ml; CD27+ 0 cells/ml). Despite resective surgery of the tongue and adjuvant concurrent chemotherapy and radiation, she was found to have widely metastatic SCC in early August 2022 (CD19+ 29 cells/ml; CD27+ 17 cells/ml; CD38+IgM-12 cells/ml). She was administered inebilizumab and then started on pembrolizumab twelve days later. Ten days after receiving her first pembrolizumab therapy, the patient developed acute onset left-sided weakness (CD19+ 4 cells/ml; CD27+ 0 cells/ml; CD38+IgM-0 cells/ml). She was found to have a large, active cervical spine lesion consistent with a new NMOSD attack; serum AQP4-IgG had increased from 1:10,000 to 1:100,000. <h3>Conclusions:</h3> An NMOSD attack occurred rapidly following pembrolizumab in a B-cell depleted patient, suggesting a role for T cell activation in relapse. ICIs should be used with caution in NMOSD patients. <b>Disclosure:</b> Dr. Upchurch has nothing to disclose. Dr. Caunt has nothing to disclose. Dr. McDermott has nothing to disclose. Dr. Bennett has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Horizon Therapeutics. Dr. Bennett has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Alexion. Dr. Bennett has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech. Dr. Bennett has received personal compensation in the range of $500-$4,999 for serving as a Consultant for TG Therapeutics. Dr. Bennett has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Reistone Bio. Dr. Bennett has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Roche. Dr. Bennett has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Antigenomycs. Dr. Bennett has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Chugai. Dr. Bennett has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Mitsubishi Tanabe. Dr. Bennett has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for EMD Serono. Dr. Bennett has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for MedEdicus. Dr. Bennett has received personal compensation in the range of $500-$4,999 for serving as a Consultant for ImCyse. Dr. Bennett has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Clene Nanomedicine. Dr. Bennett has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Bennett has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Alexion. Dr. Bennett has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Podoll. Dr. Bennett has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Patterson. The institution of Dr. Bennett has received research support from Novartis. The institution of Dr. Bennett has received research support from Alexion. Dr. Bennett has received intellectual property interests from a discovery or technology relating to health care. Dr. Bennett has received publishing royalties from a publication relating to health care. The institution of Dr. Piquet has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech. The institution of Dr. Piquet has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Dr. Piquet has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Piquet has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Piquet has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Sands Anderson PC. The institution of Dr. Piquet has received research support from Rocky Mountain MS Center. The institution of Dr. Piquet has received research support from Novartis. The institution of Dr. Piquet has received research support from Abbvie. The institution of Dr. Piquet has received research support from Roche/Genentech. The institution of Dr. Piquet has received research support from NYU. Dr. Piquet has received publishing royalties from a publication relating to health care. Dr. Piquet has received publishing royalties from a publication relating to health care. Dr. Piquet has received personal compensation in the range of $10,000-$49,999 for serving as a Litigative Consultant with US-Dept HHS/DICP.