Background: Ofatumumab is a subcutaneously administered B cell depleting agent approved by the FDA for use in patients with relapsing forms of MS. During the phase III trial program, premedications were not standardized, and systemic injection reactions were counted as related to study drug if such reactions occurred within 24 hours of the first dose of ofatumumab. Objectives: We sought to determine if a standardized premedication regimen would reduce the incidence of systemic injection reactions after the first dose administration of ofatumumab in an outpatient clinic setting. Methods: Each patient started on ofatumumab was instructed to take cetirizine 10mg the night before the scheduled first dose of ofatumumab. On the day of the injection, patients were seen in the clinic and one hour prior to injection, were given cetirizine 10mg, pepcid 20mg, and acetaminophen 500mg. Patients were also encouraged to hydrate with water throughout the five hour observation period. One hour after administration of the premedications, patients were taught how to self-inject with ofatumumab. Patients were then observed for the next five hours in clinic for any adverse reactions. Results: We instituted an initial injection monitoring protocol for the first 28 patients starting on ofatumumab. Patients initially were observed for five hours in the clinic after premedication administration. After treating 15 patients, we observed no systemic injection reactions during the first five hours post ofatumumab dosing, and subsequent patients were observed only for two hours after the initial injection. Patients were asked to report any systemic reactions after leaving the clinic through the electronic medical record or follow up phone call by clinical staff. Within 24 hours, the following systemic injection reactions were noted in the patient cohort: Fever-4, Rigors-3, Fatigue-2, Nausea-2, headache-1, vomiting-1, dizziness-1, generalized weakness-1, body pain-1. One patient had chest pain and anxiety within five minutes of injecting ofatumumab, which resolved spontaneously and was not felt to be related to the administration of ofatumumab. Conclusions: Our patient cohort during the initial injection monitoring phase tolerated ofatumumab well without any systemic injection reactions. Systemic injection reactions did occur outside of the clinic within 24 hours, but importantly resolved with supportive care, and all patients continued on therapy. The role played by the premedication regimen that we instituted in terms of mitigation and/or delay of systemic injection reactions is unclear at this time. Further research regarding this phenomenon is warranted.