OBJECTIVES: Indirect treatment comparisons must adjust for inter-study differences in design and patient characteristics, which may strongly influence outcomes. This study investigated impact of inter‑trial patient differences on the comparative effectiveness of rFVIII (ADVATE) and extended half‑life rFVIII (ADYNOVATE). METHODS: A targeted review identified Advate or Adynovate trials for which individual patient data were available (i.e., Baxalta-sponsored). Enrolled patients aged 12-65 years with severe hemophilia A (HA) who received and complied with prophylactic treatment with Advate or Adynovate were included in the analysis. A negative binomial model was used to compare number of bleeds during the first 6 months, and logistic regression was used to compare the odds of achieving ≤ 1 bleed. All regression models controlled for the effect of patient characteristics. RESULTS: Two Advate studies (Tarantino 2004, n = 55; Valentino 2012, n = 49) and one Adynovate study (Konkle 2015, n = 68) were included. Patients exhibited statistically significant differences in body mass index (p = 0.03), Caucasian race (p = 0.01), and prior medications (alimentary tract and metabolism, p < 0.01; nervous system disorder, p < 0.001). Presence of target joints was not consistently recorded so could not be included in the regression models. The incident rate ratio of annualised joint bleeding rates (AJBR) was not statistically significantly different (odds ratio 1.0 for Adynovate vs Advate; 95% CI 0.5 – 2.0). Additionally, no significant difference was observed for patients who had ≤ 1 bleed (odds ratio 0.5 for Advate vs Adynovate; 0.5– 1.2). CONCLUSIONS: No difference was found for AJBRs among adolescents and adults with severe HA treated with Advate or Adynovate targeting a trough level of 1-3%; however, clinically meaningful heterogeneity remained. Despite techniques to control for differences, patient heterogeneity remains a significant challenge for conducting comparisons of hemophilia studies.