Inclusion Criteria: * Male \>18 years of age * Severe hemophilia B (native circulating FIX activity \<1%, with or without cross reactive material) Exclusion Criteria: * Presence of neutralizing antibodies * History of hypersensitivity response or an allergic reaction to FIX or FIX products * Currently receiving long acting FIX replacement therapy * FIX mutations known to be associated with FIX inhibitors * Polymorphisms in the ZFN target region * Presence of any liver mass on MRI, or elevated alpha-fetoprotein (AFP) * Any contraindication to the use of corticosteroids for immunosuppression * Currently receiving antiviral therapy for hepatitis B or C or with history or active hepatitis B or hepatitis C or HIV-1 or HIV1/2 antibody positive. * Chronic anemia, leukopenia, or thrombocytopenia * Past medical history of active tuberculosis or significant fungal disease * Symptomatic cardiovascular disease as a co-morbid condition * Markers of hepatic inflammation or overt or occult cirrhosis * History of chronic renal disease or creatinine ≥ 1.5 mg/dL * Systemic (iv or oral) immunomodulatory agent or steroid use (topical treatment is allowed) * History of chronic infection or other chronic disorder considered an unacceptable risk * History of malignancy except for treated basal cell or squamous cell carcinoma * History of alcohol or substance abuse * Previously received gene therapy product * Participation in prior investigational drug or medical device study within the previous 3 months * History of therapeutic non-adherence * Any other reason that, in the opinion of the Investigator or Medical Monitor, would render the subject unsuitable for participation in the study