Systemic lupus erythematosus (SLE) is an inflammatory and multisystemic autoimmune disorder characterized by an uncontrolled autoreactivity of B and T lymphocytes leading to the production of autoantibodies against self-directed antigens and tissue destruction. Environmental factors, such as infections, which are an important cause of morbidity and mortality, are potential triggers of the disease. This article discusses bacterial, viral, and opportunistic microorganism infections in SLE, and the role of immunosuppressive therapy and immunodeficiencies in the disease.