The immune system can be adversely affected by a variety of extrinsic factors, including immunosuppressive drugs, exposure to harsh environmental conditions, hereditary disorders other than primary immunodeficiencies, and acquired metabolic disorders such as diabetic mellitus, with all of these resulting in conditions known as secondary immunodeficiencies. Perhaps the most well known secondary immunodeficiency is caused by HIV infection; however, the most prevalent cause of immunodeficiency worldwide is severe malnutrition, which affects as much as 50% of the population in some impoverished communities. The abnormalities of the immune system induced by secondary immunodeficiencies affect both the innate and the adaptive immunity, may be subtle, and are usually heterogeneous in their clinical manifestations. Treatment of the primary condition often results in the improvement of the compromised immune components of the disease complex. This article updates the concepts of some of the major categories of conditions that can potentially suppress the immune response, including HIV disease, to provide a conceptual frame to assess patients with suspected secondary deficiencies of the immune system.