Immunodeficiency disorders pose substantial burdens on the health-care system and the patients affected. Broadly, immunodeficiencies can be divided into primary immunodeficiency disorders (PIDDs) and secondary immunodeficiency disorders. This review will focus on PIDDs. The overall prevalence for PIDDs is estimated to be ∼1-2% of the population but may be underestimated due to underdiagnosis of these conditions. PIDDs affect males slightly more often than females. The mortality rates differ based on the specific condition but can be extremely high if the condition is left undiagnosed or untreated. The most common causes of death are infections, respiratory complications, and cancers (e.g., lymphoma). Comorbidities and complications include infection, chronic lung disease, granulomatous lymphocytic interstitial lung disease, and autoimmune disorders. The disease burden of patients with common variable immunodeficiency (CVID) is estimated to be greater than patients with diabetes mellitus and chronic obstructive pulmonary disease. PIDDs have a serious impact on the quality of life of the patients, including sleep disturbance, anxiety, and social participation as well as other psychosocial burdens associated with these disorders. The financial cost of PIDDs can be substantial, with the cost of untreated CVID estimated to be $111,053 per patient per year. Indirect costs include productivity loss and time lost due to infusion and hospital visits. Secondary immunodeficiency is not fully discussed in this review but likely contributes equally to the burden of overall immunodeficiency disorders. Management of patients with PIDDs should use a comprehensive approach, including medical, nursing, psychiatric, and quality of life, to improve the outcome.