BACKGROUND: Recent single-cell studies indicated that IL-17-producing T-cells (T17) have diverse subsets expressing IL-17A, IL-17F, or a combination of them in human psoriasis skin. However, it is unknown how T17 subsets are differently regulated by IL-23 versus IL-17A blockades. OBJECTIVE: We sought to investigate how systemic monoclonal antibody injections blocking IL-23 versus IL-17A differently modify immune cell transcriptomes in human psoriasis skin. METHODS: We analyzed a total of 93 human skin single-cell libraries, including 42 psoriasis pretreatment lesional skin, 25 psoriasis pretreatment non-lesional skin, 12 psoriasis posttreatment after IL-23 inhibition, 4 psoriasis posttreatment after IL-17A inhibition, and 10 control skin samples. RESULTS: Of the six T17 cell subsets identified, an IL17A+ IFNG+ subset and an IL17F+ IL10- subset expressed the IL-23 receptor along with other inflammatory cytokines, and IL-23 inhibition downregulated these potentially pathogenic T17 subsets. In contrast, T17 cells expressing both IL-17A and IL-17F did not express the IL-23 receptor, and the percentage of this potentially non-pathogenic T17 subset increased after IL-23 inhibition. In addition, the expression of the IL-17 negative regulation genes, such as TNFAIP3, increased in myeloid cells more after IL-23 inhibition than after IL-17A inhibition. CONCLUSIONS: This study suggests multiple immune mechanisms of how IL-23 inhibition can modify the complex inflammatory environment present in psoriatic skin, highlighting the roles of specific T17 subsets in psoriasis development and background skin protection.