Background Histamine influences T-cell reactions via histamine receptors 1 and 2. The histamine receptor 4 (H4 R) is the most recently identified histamine receptor and is also expressed on human CD4+ T cells; however, its regulation and function are unclear. Objective To investigate expression, regulation, and function of the H4 R on human CD4+ T cells. Methods Histamine receptor 4 expression was studied by real-time quantitative RT-PCR and by flow cytometry. Effects of H4 R stimulation on induction of the signal transduction molecules activator protein 1 (AP-1) and nuclear factor-κB (NF-κB) were determined by electrophoretic mobility shift assay and on cytokine production by RT-PCR and ELISA. Results Histamine receptor 4 mRNA and protein were expressed by CD4+ T cells and upregulated by IL-4. Its expression was higher on TH 2 cells than TH 1 cells and naive T-cells. H4 R agonists (clobenpropit and 4-methylhistamine) induced AP-1 in TH 2 cells but not in TH 1 cells. This effect was blocked by the H4 R antagonist JNJ7777120. H4 R agonists upregulated IL-31 mRNA in PBMCs and TH 2 cells, a cytokine that has been associated with TH 2 cells and the induction of pruritus. IL-31 mRNA induction by H4 R stimulation was pronounced in PBMCs from patients with atopic dermatitis. Expression of IL-4, IL-5, and IL-13 was not altered by the H4 R. Conclusion Human CD4+ T cells express a functional H4 R. The receptor is upregulated under TH 2 conditions, and its stimulation leads to induction of AP-1 and IL-31.