A number of primary immunodeficiencies are associated with autoimmune phenomena, e.g. Wiskott-Aldrich Syndrome, Common Variable Immunodeficiency and Hyper-IgM Syndrome. The common denominator is a dysregulation of immune responses affecting T and B cells with central and/or peripheral tolerance mechanisms being disturbed. Autoimmunity and autoinflammation may also occur in atypical phenotypes of combined immunodeficiencies (CID) usually associated with severe infectious complications. These unexpected presentations of classical CID are very instructive in how low numbers of T and B cells go hand in hand with skewing of lymphoid repertoires and function. The resulting immune dysregulation may lead to self-reactivity with organ damage and malignancy.