OBJECTIVES: For people with hemophilia A, factor VIII (FVIII) prophylaxis is burdensome, potentially leading to poor compliance.  Treatment adherence and outcomes may be improved with drugs requiring less frequent infusions.  In the absence of head-to-head direct comparative evidence from clinical trials, this analysis indirectly compared the prophylactic efficacy of recombinant FVIII Fc fusion protein (rFVIIIFc) with the published results of current rFVIII products and simulated effects of potential differences in real-world compliance between regimens. METHODS: rFVIIIFc and rFVIII were indirectly compared using data from previously treated subjects in the A-LONG phase 3 study (rFVIIIFc; individualized arm) and published clinical studies of routine prophylaxis (rFVIII; identified by literature search).  Efficacy was compared using reported differences in mean annualized bleed rates (ABRs) for individual and pooled results using meta-analysis with random effects.  Unreported standard deviations of ABR were estimated assuming a Poisson distribution and adjusted for over-dispersion.  A model was developed to assess the effect of compliance changes on ABR. RESULTS: This analysis included published results from the A-LONG study (severe hemophilia; rFVIIIFc; Mahlangu 2013) and 4 studies of rFVIII (moderate/severe hemophilia; Advate^®: Tarantino 2004, Shapiro 2003, and Valentino 2012; Xyntha^®: Recht 2009).  Infusion frequencies were 1.4-2.4 (median 2.0) times/week for rFVIIIFc and 2.3-4 times/week for rFVIII.  Mean ABR for rFVIIIFc was 2.9; the pooled mean ABR estimate for rFVIII was 4.8 (I =44.2%, ΔABR=1.8; P=0.003).  Simulations showed that statistically significant improvements in mean ABR would result from improving compliance with rFVIIIFc by ≥6-12 percentage points. CONCLUSIONS: Results of this unadjusted indirect comparison of clinical studies suggest that routine prophylaxis with rFVIIIFc may result in a lower mean ABR than that of other rFVIII products examined.  Moreover, potential improvements in compliance associated with less burdensome dosing requirements, as suggested by studies in other chronic diseases, may result in better effectiveness with rFVIIIFc.