Opportunistic diseases have been and still are a major cause of HIV associated morbidity and mortality. Patients with undiagnosed HIV infection often present with symptoms of opportunistic infections. Therefore, all clinicians should know their clinical presentations. Patients with severe immunodeficiency, manifested by low CD4-lymphocyte count, should receive primary prophylaxis against Pneumocystis jiroveci, T. gondii und M. avium. After successful initial treatment of opportunistic infections maintenance therapy is indicated. The introduction of potent antiretroviral combination therapy has led to a decline of incidence and letality of most opportunistic diseases and allows discontinuation of established primary prophylaxis and maintenance therapy if a durable rise of CD4-lymphocyte count can be achieved. The improvement of immunocompetence due to antiretroviral therapy is also associated with new clinical manifestations of opportunistic infections, the immune reconstitution inflammatory syndromes. The framework of the multicenter Swiss HIV Cohort Study with its detailed documentation of opportunistic diseases has allowed several important studies and analyses that have had a worldwide influence on the management of these diseases.