Background: Hemophilia A is an X-linked congenital bleeding disorder caused by deficient or defective factor VIII (FVIII), characterized by spontaneous or traumatic bleeding into joints, muscles, and body cavities. The burden of disease is high, as prophylaxis for bleed prevention requires several weekly intravenous factor infusions which are expensive and inconvenient. By adulthood, fewer than 50% comply and many develop pain, joint degeneration, and disability. For the 30% who develop inhibitors, requiring bypass therapy, which is associated with poor response, frequent hospitalization, and high cost. The bispecific monoclonal antibody emicizumab is licensed to prevent bleeds in hemophilia A (HA) and HA with inhibitors (HA-I). While it mimics FVIII by bridging FIXa and FX, it differs from FVIII biochemically, with no phospholipid binding and limited self-regulation. Thus, whether bleed frequency and severity, long-term joint health, and quality of life are comparable to FVIII is unknown. Methods: We reviewed outpatient medical records of HA and HA-I cared for at Hemophilia Center of Western Pennsylvania, switched to emicizumab between November 2017 and May 2019. This was an expedited study approved by the University of Pittsburgh IRB, PRO1800098. Means, medians, and standard deviations or frequencies were determined for clinical variables, including age race, genotype, reason for switching, bleeding events, surgical events, and treatment rating. Group comparisons were by Student's t test for continuous data, or chi-square or Fisher's exact test for discrete data. A p-value of <0.05 was considered significant. Results: A total of 42 patients initiated emicizumab during outpatient comprehensive clinic, including 18 (42.9%) HA and 24 (52.1%) HA-I. Of these, 17 (47.3%) were <18 years, 38 (90.5%) were Caucasian, and 34 (80.9%) had severe disease, FVIII<0.01 IU/ml, similar between groups. Of the 20 on whom hemophilia genotypes were known, 7 (35.0%) had missense mutations, 7 (35.0%) had intron 22 inversion mutations, 3 (15.0%) had deletion mutations, 2 (10.0%) had nonsense mutations, and 1 (5.0%) had an intron 1 mutation, with no difference in distribution between HA and HA-I. Among 24 HA-I, the median peak titer was 16 BU (0.7-2056); of these, immune tolerance induction (ITI) had been successful in 11, unsuccessful in 10, and never attempted in 3. Emicizumab was given at 1.5 mg/kg/wk subcutaneously (SQ), following a 4-week induction with 3.0 mg/kg/wk, and patients or parents continued weekly dosing at home. The most common reasons for switching to emicizumab was to control breakthrough bleeding in 79.3% or to avoid intravenous/port access in 20.7%. Licensure for emicizumab in HA-I patients occurred before licensure for HA, so emicizumab was used longer in HA-I than HA, 12.3 vs. 4.8 months, p=0.001. Overall, of the 42 patients, 14 (33.3%) experienced at least one bleeding episode, not different between groups, p=0.724. Of these, 11 (44.0%) were joint bleeds, similar between HA and HA-I, p=0.780, with an annualized bleed rate (ABR), 0.9 ± 0.3, not different between groups, 0.9 ± 0.3 vs. 0.5 ± 0.1, p=0.251; and an annualized joint bleed rate (AJBR), 0.1 ± 0.1 vs. 0.2 ± 0.1, p=0.774. Breakthrough bleeds were unrelated to inhibitor titer, peak or pre-emicizumab, p=0.061. The 15 surgeries in 10 patients (4 HA, 6 HA-I) were well tolerated, with no bleeding in 11/15 (73.3%). Six were managed with preoperative factor, of which 4 had postoperative bleeding, including 1 HA and 3 HA-I, p=0.369. One HA-I, receiving rFVIIa for hip replacement, developed postoperative bleeding for which FEIBA was given. Despite emicizumab discontinuation 30 days preoperatively, he developed priapism, local thrombotic microangiopathy (TMA), and urethral abscess requiring urethroplasty. Hemostasis was accomplished with porcine rVIII and red cell transfusion. Overall, 5 (11.9%) experienced complications, including local skin reactions in 3 and headache and thrombosis (above) in 1 each (2.4%), not different between HA and HA-I, p=0.225. Overall, 17 of 20 (85.0%) experienced improved health. Discussion: This study indicates the majority of HA and HA-I switching to emicizumab experience low ABR, infrequent surgical bleeding, and subjective improvement in health. Postoperative thrombosis/TMA suggests FEIBA should be avoided for at least 6 months after emicizumab discontinuation, during which it may still be detected. Disclosures Xavier: Bioverativ/Sanofi: Research Funding. Seaman:Takeda: Consultancy; Bayer: Consultancy; Genentech: Consultancy; Spark Therapeutics: Consultancy. Ragni:Alnylam/Sanofi: Other: Advisory Board, Research Funding; BioMarin: Other: Advisory Board, Research Funding; Bioverativ/Sanofi: Other: Advisory Board, Research Funding; OPKO: Research Funding; Sangamo: Research Funding; Shire/Takeda: Other: Advisory Board, Research Funding; Spark Therapeutics: Other: Advisory Board, Research Funding.