Mycoplasma pneumoniae has been recognized to be involved in several extra-pulmonary diseases, but the underlying immunologic mechanisms are still largely unknown. Recently, we observed a significant elevation of serum Immunoglobulin E (IgE) in a small group of these children. Here, we assessed total serum IgE levels in children affected with Mycoplasma pneumoniae-related extra-pulmonary diseases. We prospectively collected the data of 162 children admitted to the hospital (because of respiratory infections or extra-pulmonary diseases) who were evaluated for Mycoplasma pneumoniae serology and total serum IgE levels, concomitantly. Based upon clinical and serology aspects, 3 groups of children were identified: I) with non-mycoplasma respiratory disease; II) with mycoplasma-related respiratory diseases; III) with extra-pulmonary diseases related to concomitant/recent Mycoplasma pneumoniae infection. Interestingly, children with Mycoplasma pneumoniae-related extra-pulmonary diseases showed a significant elevation of total serum IgE. In particular, patients developing Mycoplasma pneumoniae-related extra-pulmonary diseases (group III) showed significantly higher level of IgE than both previous groups (p<0.001 vs. group I; p<0.01 vs. group II). In conclusion, hospitalized children diagnosed with Mycoplasma pneumoniae-related extra-pulmonary diseases resulted to have significantly increased serum IgE compared to children developing respiratory illnesses only.