Treatment decisions made in clinical practice, based on current guidelines, often conflict with decisions by third-party payors that restrict the ability of patients with primary immunodeficiency disease (PI) to adhere to appropriate treatment. This is seen by many physicians as potentially placing the health of patients at risk. Key treatment decisions challenged by third-party payors and discussed here include dosing, product safety, and routes of administration. Data on safety issues emphasize that IgG products are not generic drugs and each of the products currently licensed by the Food and Drug Administration (FDA) must be regarded as an individual therapy, given the products' different manufacturing processes and stabilizing ingredients. The issue of switching patients to a different product needs careful consideration as evidence shows that infusion-related adverse events in many patients are frequently related to this activity. Decisions regarding the route of therapy should also be individualized to the patient, weighing such factors as side effects, adherence with therapy, and lifestyle.