Primary immunodeficiency diseases of the adult are rare disorders, but often lead to serious consequences. Therefore an early diagnosis is critical. The variety in the clinical presentation, the complexity of the immune system and the ongoing discovery of new defects render it a difficult area for the involved physician. Due to the often imprecise complaint of a weak immune system the primary task is the identification of patients with true immunodeficiency. Subsequently, the immune defect needs to be identified in collaboration with a center for immunodeficiency disorders. The diagnostic procedure is dependent on the pattern of infections and follows a defined series of steps. This procedure should prevent costly diagnostic evaluation when not indicated, and also prevent the delayed diagnosis of patients with manifest immunodeficiency disease.