Inclusion Criteria:

• Males ≥ 18 years of age with hemophilia A and residual FVIII levels ≤ 1 IU/dL as evidenced by medical history, at the time of signing the informed consent.
• Must have been on prophylactic FVIII replacement therapy for at least 12 months prior to study entry. High-quality, well-documented historical data concerning bleeding episodes and FVIII usage over the previous 12 months must be available.
• Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 exposure days (EDs).
• No history of FVIII inhibitor, and results from a Bethesda assay with Nijmegen modification of less than 0.6 Bethesda Units (BU) on 2 consecutive occasions (the most recent one of which should be tested at the central laboratory) at least one week apart within the past 12 months
• HIV positive patients may be enrolled, only if the patient has a CD4 count > 200/mm3 and an undetectable viral load.

Exclusion Criteria:

• Detectable pre-existing antibodies to the AAV5 capsid.
• Any evidence of active infection or any immunosuppressive disorder, except for HIV infection as described in the inclusion criterion above.
• Significant liver dysfunction with any of the following abnormal laboratory results:
  • ALT (alanine transaminase) or AST >2X ULN;
  • Total bilirubin >2X ULN;
  • Alkaline phosphatase >2X ULN; or
  • INR (international normalized ratio) ≥ 1.4.

Subjects whose liver laboratory assessments fall outside of these ranges may undergo repeat testing and, if eligibility criteria are met on retest, may be enrolled after confirmation by the Medical Monitor. In addition, subjects with abnormal laboratory results related to confirmed benign liver conditions (eg, Gilbert's syndrome) are considered eligible for the study notwithstanding their abnormal laboratory results and may be enrolled after discussion with the Medical Monitor.

• Prior liver biopsy showing significant fibrosis of 3 or 4 as rated on a scale of 0-4 on the Batts-Ludwig (Batts 1995) or METAVIR (Bedossa 1996) scoring systems, or an equivalent grade of fibrosis if an alternative scale is used.
• Evidence of any bleeding disorder not related to hemophilia A.
• Platelet count of < 100 x 10^9/L.
• Creatinine ≥ 1.5 mg/dL.
• Liver cirrhosis of any etiology as assessed by liver ultrasound.
• Chronic or active hepatitis B as evidenced by positive serology testing and confirmatory HBV DNA testing. Refer to the Centers for Disease Control (CDC) table for the interpretation of serological test results in the Laboratory Manual.
• Active Hepatitis C as evidenced by detectable HCV RNA or currently on antiviral therapy.
• Active malignancy, except non-melanoma skin cancer.
• History of hepatic malignancy.
• History of arterial or venous thromboembolic events (eg, deep vein thrombosis, nonhemorrhagic stroke, pulmonary embolism, myocardial infarction, arterial embolus), with the exception of catheter-associated thrombosis for which anti-thrombotic treatment is not currently ongoing.
• Known inherited or acquired thrombophilia, including conditions associated with increased thromboembolic risk, such as atrial fibrillation.