BACKGROUND: Emicizumab prophylaxis is restricted to severe hemophilia A in the UK. Treatment choice and safety remain a matter of debate. OBJECTIVES: This study was conducted to investigate factors influencing treatment choice, continued use, safety, and clinical outcomes associated with emicizumab in a national cohort of persons with severe hemophilia A without current inhibitors. METHODS: A 3-year study was conducted in 618 persons with severe hemophilia A who switched to emicizumab and 413 who continued factor (F)VIII prophylaxis. Outcome measures included annualized bleed rates (ABRs), the Hemophilia Joint Health Score, and health-related quality of life. RESULTS: Switchers and nonswitchers had a similar median age (26 and 28 years, respectively). Switchers had a significantly higher median (IQR) ABR than those continuing FVIII prophylaxis, but a significantly lower proportion had an inhibitor history (13.6% vs 20.5%; P = .0005). Thirty-one adverse events were reported, including 1 thrombosis (0.2%), 8/84 recurrent inhibitors (9.5%), 1 neutralizing antidrug antibody (0.2%), and 14/618 (2.3%) patients discontinued emicizumab. A higher prestudy median (IQR) ABR was observed in switchers compared with nonswitchers (2.05 [0.43, 6.06] vs 0.68 [0, 2.7]), reducing to a median (IQR) of 0 (0, 0) with emicizumab prophylaxis. The proportion with a zero-treated bleed rate increased from 35% to 71% (P = .001). An 82% reduction in bleeding into target joints was observed in favor of emicizumab. A modest (Δ= -2; P = .02) improvement in the total Hemophilia Joint Health Score was observed. CONCLUSIONS: Emicizumab selection was influenced by ABR and inhibitor history but not age. Emicizumab was generally well tolerated, with only 2.3% discontinuing the drug. A significant within-person improvement in all bleeding outcomes was observed with emicizumab.