BACKGROUND: Recent single-cell studies indicated that IL-17-producing T cells (T17) have diverse subsets expressing IL-17A, IL-17F, or a combination in human psoriasis skin. However, it is unknown how T17 subsets are differently regulated by IL-23 versus IL-17A blockade. 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 nonlesional skin, 12 psoriasis posttreatment after IL-23 inhibition, 4 psoriasis posttreatment after IL-17A inhibition, and 10 control skin samples. CLINICALTRIALS: gov NCT04630652. RESULTS: Of the six T17 subsets identified, an IL17A 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.