The development of effective, safe, liquid intravenous immunoglobulins (IVIG) preparations has represented a major therapeutic advancement in the treatment of patients with antibody deficiencies. Flebogamma® 5% was the first liquid IVIG licensed in Europe that has been widely used in the treatment of immunodeficiency diseases. It has been proven to have an excellent efficacy and safety profile. Flebogamma® 5% dual inactivation and filtration (DIF) is a newly developed IVIG preparation that shares formulation characteristics and identical biochemical and stability profiles with Flebogamma® 5%. In addition to pasteurization, already performed in Flebogamma® 5%, solvent-detergent treatment and sequential nanofiltration through filters with pore sizes of 35 nm followed by 20 nm have been added to further enhance the pathogen safety margin. The purpose of this study was to evaluate the efficacy, safety, and pharmacokinetics of Flebogamma® 5% DIF for immunoglobulin replacement therapy in patients with primary immunodeficiency diseases (PID). Flebogamma® 5% DIF was administered at seven clinical sites to 46 subjects with well-defined primary immunodeficiency diseases at a dose of 300–600 mg/kg every 21–28 days for 12 months. The serious bacterial infection rate was 0.021/subject/year. The incidence of adverse events considered potentially related to Flebogamma® 5% DIF during or within 72 h after completing an infusion was approximately 10%. The half-life in serum of the administered IgG was around 31 days. In summary, Flebogamma® 5% DIF is efficacious and safe, has good pharmacokinetic properties, is well-tolerated and maintains the profile of Flebogamma® 5% for the treatment of patients with primary humoral immune deficiency diseases.