Mucopolysaccharidosis Type II is a hereditary lysosomal storage disease characterized by deficiency in the enzyme iduronate 2-sulfatase (IDS). IDS is critical in the breakdown of sulfated glycosaminoglycans and its deficiency leads to an accumulation of these compounds across various tissue types resulting in multisystemic dysfunction. Intravenous administration of recombinant IDS (idursulfase) substantially improves patients’ quality and length of life. However, recombinant IDS delivered intravenously is sequestered in the liver and respiratory failure remains as the leading cause of death for patients independent of idursulfase treatment, which suggests insufficient delivery to the lungs. This study aimed to assess a novel method of idursulfase administration by nebulizer in combination with intravenous treatment and determine if this route of administration may improve lung delivery of idursulfase and overall pathology. To fulfill this aim, whole body IDS knockout mice underwent twelve weeks of intravenous or combination treatment. Liver and lung tissue were harvested seven days after the last treatment. IDS activity, histological markers, and global proteomics from treated groups were compared to untreated knockouts or wild-type mice. Increased enzyme activity and histological measurements indicated augmented delivery to the liver with the combined treatment, but lung enzyme activity with each treatment was similar to untreated animals. However, proteomics data demonstrated that both treatments attenuated key features of the disease, although it is unclear whether the addition of nebulized administration improved efficacy in the lungs.