The transcription factor retinoic acid-related orphan receptor 2 (RORC2/RORγT) mediates interleukin (IL)-17A and IL-17F expression. IL-17A plays a central role in the pathogenesis of several inflammatory disorders, including psoriasis. The RORC2 inhibitor PF-06763809 has been hypothesized to inhibit IL-17A production in T-helper 17 (Th17) cells, thereby reducing psoriasis symptoms.To assess the safety, tolerability, and effect on skin infiltrate thickness of PF-06763809 in participants with mild/moderate chronic plaque psoriasis.Randomized, double-blind, first-in-human study (NCT03469336). Participants received each of the following treatments once daily for 18 days: three topical doses (2.3%, 0.8%, 0.23%) of PF-06763809, vehicle, and two active comparators (betamethasone and calcipotriol). Primary endpoints included change from baseline in psoriatic skin infiltrate thickness (echo-poor band [EPB] by ultrasound) at Day 19 and safety. Change in psoriasis-associated gene expression (Day 19), evaluated by RT-PCR of skin biopsies, was an exploratory endpoint.Seventeen participants completed the study. The change from baseline in the EPB on Day 19 for all three doses of PF-06763809 was not significantly different from that of vehicle (P > 0.05). A significant reduction in EPB from baseline was observed with betamethasone on Day 19 relative to all other treatments (P < 0.0001). Treatment-related adverse events were mild/moderate. There were no significant differences in gene expression on Day 19 between vehicle and PF-06763809-treated skin lesions.Using a psoriasis plaque test design, PF-06763809 was well tolerated with an acceptable safety profile in participants with psoriasis, but without reduction in skin infiltrate thickness or disease biomarkers.