Naturally occurring autoantibodies (NAbs) with germline or close to germline configurations are specific to self- and altered self-components and they exist in the serum of healthy individuals, independent of deliberate immunization with a target antigen. Human intravenous immunoglobulin (IVIg) consists of pooled immunoglobulin (IgG) from several thousand healthy volunteers. In addition to immune deficiency, IVIg is used in the treatment of several autoimmune and inflammatory conditions. The polyreactive, low- to moderate-affinity but high-avidity NAbs are an important part of the composition of IVIg. It is well established that NAbs play a significant role in maintaining tissue and immune homeostasis in a healthy individual. It is thus conceivable that NAbs present within IVIg may participate in exerting the beneficial effects observed during the course of treatment of patients with autoimmune and inflammatory diseases. Understanding the mechanisms by which NAbs operate under different clinical settings is of critical significance. In this chapter, we summarize the roles of NAbs in IVIg. © 2014 Elsevier B.V. All rights reserved.