BackgroundReal-world experience with efmoroctocog alfa (a recombinant factor [F]VIII Fc [rFVIIIFc])/eftrenonacog alfa (recombinant factor IX Fc [rFIXFc]) is needed to bridge evidence gaps. ObjectivesTo describe rFVIIIFc/rFIXFc usage and effectiveness over a 24-month prospective period. MethodsPREVENT (NCT03055611), a noninterventional study across 25 German hemophilia treatment centers, enrolled previously treated persons with hemophilia A/B (all ages/severities) on individualized rFVIIIFc/rFIXFc prophylaxis before/at enrollment. Primary endpoints included annualized bleeding rate (ABR), injection frequency (IF), and factor consumption. Additionally, up to 12 months of retrospective FVIII/FIX data were collected. Physician/patient satisfaction and safety outcomes were assessed. ResultsOverall, 47 of 150 patients received ≥1 rFVIIIFc/rFIXFc dose with median prospective follow-up of 20.6/21.0 months, respectively. rFVIIIFc/rFIXFc demonstrated low median ABR (0.5/1.7), annualized IF (121.8/52.2 injections/y), and FC (4611.7/2423.9 IU/kg) in line with product labels. Compared with previous FVIII/FIX, there was a 56.0% reduction in ABR for rFVIIIFc (rate ratio, 0.44; 95% CI, 0.31-0.64), with no change for rFIXFc (rate ratio, 0.93; 95% CI, 0.66-1.31); rFVIIIFc/rFIXFc reduced annualized IF (rFVIIIFc, mean difference, −31.7; 95% CI, −40.3 to −23.1; rFIXFc, mean difference, −37.3; 95% CI, −46.9 to −27.8), while FC remained stable (rFVIIIFc, +374.1; 95% CI, +46.8 to +701.3; rFIXFc, +503.9; 95% CI, +95.4 to +912.4). Most physicians/patients were satisfied/highly satisfied with rFVIIIFc/rFIXFc. rFVIIIFc/rFIXFc were well tolerated, with no inhibitor development or treatment-related serious adverse events. ConclusionReal-world PREVENT data complement phase 3 trials and show that individualized rFVIIIFc/rFIXFc prophylaxis provided stable bleed protection with low IF and maintained FC. Compared with previous FVIII, ABR was considerably reduced with rFVIIIFc, with stable annualized FC. For rFIXFc, bleed protection was maintained vs previous FIX while reducing annualized IF.