Background: Interleukin-31(IL-31) is Th2-cell-derived cytokine which can induce skin lesions such as atopic dermatitis(AD). IL-31 mRNA and protein expressions are largely restricted to CD4+ T cells, particularly CD45RO+ CLA+ T cells. Histamine-4-receptor(H4R) is upregulated under Th2 conditions, and H4R stimulation leads to the induction of IL-31 in vitro. However, the association between IL-31 and H4R in human has not been reported. Objectives: The purpose of the present study is to evaluate the hypothesis that H4R+ CLA+ CD45RO+ T cells produce IL-31 predominantly. Methods: Immunofluorescence studies were done on biopsy specimens of 5 AD, 3 prurigo nodularis and 3 controls. Blood samples were collected from 12 AD patients and controls. The H4R+ CLA+ CD45RO+ T cells were sorted by fluorescence-activated cell sorting (FACS). The level of IL-31 in the culture supernatant were measured by enzyme-linked immunosorbent assay. Results: Under HPF, the IL-31+ H4R+ cell counts were 12.9, 6.7 and 0.0 in AD, prurigo nodularis, and controls, respectively (p<0.01). The result of FACS showed that the proportion of H4R+ CLA+ CD45RO+ T cells were 25.6 and 16.4 % in AD and control, each. These cells showed increased production of IL-31 in both stable and stimulated status in AD group(p<0.001), but not in control group. Conclusion: According to our study, H4R+ CLA+ CD45RO+ T cells are a major source of IL-31, and this subset may be targets for the treatment of IL-31 induced pruritus.