Inhalation therapy represents a promising strategy for the delivery of biopharmaceuticals for the local treatment of respiratory diseases. Purified polyclonal serum immunoglobulin G (IgG), also known as IVIg products, exhibit a solid reactivity against common viral and bacterial antigens. However, IVIg are usually delivered intravenously or subcutaneously, thus, not at the sites where most infections originate. Accordingly, a respiratory mucosal delivery of IVIg may have the potential to prevent infections at the mucosal barrier. To evaluate the feasibility and efficacy of inhalable IVIg for the prevention and therapy of respiratory infections, this study examined nebulization and its impact on protein quality, as well as potential effects on in vitro cytotoxicity and immunogenicity. IVIg were formulated with either 0, 200, or 400 μg/mL of polysorbate 80 (PS80). Formulation with polysorbate 80 resulted in less IgG aggregation during nebulization and thereby reduced in vitro immunogenicity. Further, the transepithelial transport was analyzed using two different airway epithelial models, with no effects observed due to either nebulization or formulation. Finally, the efficacy of formulated aerosolized IVIg against Streptococcus pneumoniae TIGR4 model bacteria was assessed. The results demonstrated a dose-dependent binding of relevant S. pneumoniae antigens and efficient dose-dependent opsonophagocytosis of S. pneumoniae. In conclusion, this study indicated the promising potential of inhaled polyclonal IVIg as an effective therapy against respiratory infections.