Autosomal‐dominant hyper‐IgE syndrome (AD‐HIES) is a primary immunodeficiency caused by STAT3 mutations. This inherited condition is characterized by eczema, staphylococcal cold abscesses and recurrent pulmonary infections. Given that STAT3 is involved in IL‐10 signaling, we examined the immunoregulatory role of IL‐10 in inflammation by studying the effects of IL‐10 on monocytes, neutrophils and monocyte‐derived DCs from HIES subjects. Analysis of gene expression in PBMCs and neutrophils isolated from HIES patients and stimulated with LPS in the presence of IL‐10 showed reduced expression of IL1RN, which encodes IL‐1 receptor antagonist (IL‐1ra), and SOCS3 mRNA but increased CXCL8 mRNA expression. Moreover, secretion of the anti‐inflammatory protein IL‐1ra was reduced in AD‐HIES patients. DCs from HIES patients secreted higher levels of TNF‐α, IL‐6 and, to a lesser extent, IL‐12 when these cells were cultured in the presence of IL‐10. These results suggest that IL‐10 activity is affected in myeloid cells (e.g. monocytes, DCs) of HIES patients. Impairment of IL‐10 signaling in patients with AD‐HIES might result in an altered balance between pro‐inflammatory and anti‐inflammatory signals and might lead to persistent inflammation and delayed healing after infections.