Background: While interferon alfa has been used for decades as a cytoreductive agent in myeloproliferative neoplasms (MPNs), tolerability and need for frequent parenteral administration have limited its widespread adoption. Ropeginterferon Alfa-2b-njft (ropeg) is monopegylated extended half-life interferon alpha product that received FDA approval for treatment of polycythemia vera (PV) in November 2021. A phase III clinical trial has demonstrated efficacy and tolerability of this novel agent as compared to hydroxyurea (HU) in PV patients with indication for cytoreductive therapy. Real-world experience (RWE) assessment of a newly available pharmaceutical can yield important insights regarding barriers to access, clinical feasibility, and usage in populations not yet evaluated in clinical trial. In this single institution cohort, we report the first RWE using ropeg for patients with MPNs, including essential thrombocythemia (ET), in the United States. Methods: Patients presenting to an MPN clinic at an academic medical center were evaluated for initiation of ropeg based individualized assessment, with patients engaged in shared decision-making regarding risks and benefits. Patients were screened for autoimmune, neuropsychiatric, or endocrine disorder on basis of history and limited laboratory investigation as appropriate, including thyroid stimulating hormone, triglycerides, and anti-nuclear antibody testing. The treating physician and pharmacist provided pre-treatment counseling including review of potential toxicities, administration teaching, and financial considerations. Patients on HU were started on a dose 50mcg every 2 weeks via subcutaneous injection with subsequent HU tapering; patients not on HU were started 100mcg every 2 weeks. Ropeg dosing was increased to target hematologic response. Complete blood counts and comprehensive metabolic panels were ordered every 2 weeks until hematologic response achieved, with less frequent monitoring thereafter. Results: Between December 2021 to June 2022, 13 patients with JAK2 V617F positive MPNs have been started on ropeg. Four patients were unable to start ropeg due to payor denial of coverage and ineligibility for manufacturer patient assistance programs. Patients were predominantly female (10/13, 77%) with average age of 60.9 years (range 36-73 years). Seven patients had PV (transformed from ET in 2 cases), 5 patients had ET, and 1 patient had post-ET myelofibrosis. Mean pre-treatment hematocrit, platelet count, and WBC were 42.5% (range 34.3% - 51.5%), 630 *109/L (range 127-2065*109/L), and 7.0*109/L (range 2.5 - 13*109/L) respectively. At treatment start, 7 patients were on HU (either alone or in combination with therapeutic phlebotomy (TP)), 1 was on TP alone, 1 was on ruxolitinib, 1 was on peginterferon alfa-2a, and 3 were on no cytoreductive treatment. Reasons for switching to ropeg included poor tolerance or efficacy of prior therapy (6/13, 46%), patient interest in potential disease modifying properties of interferon (6/13, 46%), and, in the case of patient on peginterferon alfa-2a, ease of administration (1/13, 7.6%). Patients received medication through insurance approval with copay assistance (11/13, 85%) or through the manufacturer patient assistance program (2/13, 15%). Average time to receipt of medication from prescription submission was 25 days. At mean follow-up time of 12.9 weeks, all patients remain on treatment. One patient required treatment interruption due to severe fatigue, two patients deferred scheduled doses due to cold-like symptoms. While efficacy data is immature, one patient with PV and 2 patients with ET obtained a hematologic response (hematocrit <45% without phlebotomy in 3 months and platelet count <450), with mean response time 6.9 weeks (range 5.7 -7.7). Two patients experienced rebound in hematocrit after HU stop and are requiring TP as bridging therapy. Conclusions: Medication access, patient counseling, and symptom and laboratory monitoring must be addressed in translating clinical trial findings to clinical practice with ongoing evaluation of drug efficacy and safety. In a single institution analysis, 13 patients with MPNs, including 5 patients with ET, were started on ropeg with good initial tolerance at mean follow-up of 12.9 weeks. Lengthy insurance approval process and payor coverage denials limit medication access.