Objective: Allergic diseases, infections, parasitic infections, hematologic malignancies, chronic lung diseases, inflammatory diseases, cystic fibrosis, nephrotic syndrome and primary immunodeficiencies (PIDs) are the main disorders in the differential diagnosis of elevated serum IgE levels. The aim of this study was to evaluate the differential clinical diagnosis of patients whose serum IgE levels were found to be above 2000 IU/ml when measured at the pediatric allergy and immunology outpatient clinics of our hospital. Materials and Methods: This was a retrospective study of children aged between 2 months to 18 years referred to the Pediatric Allergy and Immunology clinics and evaluated at our hospital between October 2010 and March 2021. Results: In the 480 patients with serum total IgE levels exceeding 2000 IU/ml in this study, allergic diseases were observed in 313 (65.2%) patients, primary immunodeficiencies in 28 (5.8%), infectious diseases in 12 (2.4%), hematological diseases in 14 (2.8%), rheumatologic diseases in 5 (1%), and other diseases in 2 (0.4%), while 113 (23.5%) patients were undefined. Conclusion: This study revealed that allergic diseases were the most common cause of extremely elevated serum IgE levels, while 5.8% of the patients were diagnosed with primary immunodeficiencies. Our study indicates that primary immunodeficiencies, although rare, should be kept in mind in patients with a serum total IgE above 2000 IU/ml.