Primary immunodeficiency disease (PIDD) comprises a group of congenital defects of the immune system that cause an enhanced susceptibility to recurrent and often severe infections. Infectious disease specialists may very well diagnose and participate in the management of patients with PIDD because they are likely to present with frequent and/or severe infections or infections caused by pathogens that are not harmful to healthy people. A PIDD may be suspected after assessment of patient history and physical examination, but laboratory testing is needed to establish a specific diagnosis. Referral to an immunologist for management of a treatment plan is often recommended after a confirmed diagnosis. The standard treatment for humoral or antibody deficiencies, the most common types of PIDD, is immunoglobulin replacement therapy with purified human serum immunoglobulin, which has been shown to reduce significantly the frequency and severity of infections as well as long-term complications of PIDD. The 2 most frequently used routes for administering immunoglobulin replacement therapy are intravenous, typically given once a month, and subcutaneous, usually once weekly. Treatment with either route is effective and well tolerated, although subcutaneous therapy can be self-administered at home. An increased awareness of the signs and symptoms of PIDD, an understanding of appropriate referral, and effective treatment are essential to improving the health and quality of life of patients with PIDD.