Abstract: Objective To study the role of cutaneous nerve and protease activated receptor 2 （PAR2） in the development of pruritus in atopic dermatitis （AD）. Methods Dermal sheets were prepared from chronically pruritic skin lesions of 7 patients with AD, as well as from the normal skin of 7 healthy human controls. Double labeled immunofluorescence was performed using mouse anti-protein gene product 9.5 （PGP9.5） monoclonal antibody and rabbit anti-substance P （SP） polyclonal antibody to observe the morphological changes in cutaneous nerve fibers, and Image-Pro Plus 6 software was used to semiquantitively assess the length, diameter of nerve fibers, integral optimal density of PAR2 and SP in dermal sheets. Results Immunofluoresence double staining showed that PAR2 co-expressed with PGP9.5 or SP in cutaneous nerve fibers. Compared with the normal control skin, both the total length and average diameter of PGP 9.5- expressing nerve fibers were increased （11051.8 ± 1900.9 μm vs 7264.0 ± 2659.9 μm, 4.23 ± 0.15 μm vs 3.95 ± 0.15 μm, both P < 0.01） in pruritic lesions, while only the average diameter of SP-expres- sing nerve fibers was up-regulated （3.99 ± 0.20 μm vs 3.80 ± 0.07 μm, P < 0.05）, and the total length of them remained unchanged （4304.7 ± 1455.0 μm vs 3380.0 ± 1735.4 μm, P > 0.05）. Also, increased integral optimal density was observed for SP and PAR in pruritic lesions in comparison with the normal control skin （27.71 ± 16.52 vs 12.63 ± 4.31, 35.99 ± 8.63 vs 22.69 ± 9.56, both P < 0.05）. Conclusion Our results indicate a hyper- plasia of cutaneous nerve fibers in chronic itchy skin lesions of AD and an increase in the expression of PAR2 and SP in the cutaneous nerve fibers, suggesting that the signal enhancement in PAR2 pathway may be related to the mechanism of pruritus in patients with AD.