Significantly more patients with moderate-to-severe plaque psoriasis treated with the interleukin (IL)-17A inhibitor ixekizumab vs. the IL-23p19 inhibitor guselkumab in the IXORA-R head-to-head trial achieved 100% improvement in Psoriasis Area and Severity Index (PASI 100) at Week 12.To compare skin and nail clearance and patient-reported outcomes for ixekizumab vs. guselkumab, up to Week 24.IXORA-R enrolled adults with moderate-to-severe plaque psoriasis (static Physician's Global Assessment [sPGA] ≥3, PASI ≥12, and BSA ≥10%). Statistical comparisons were performed using the Cochran-Mantel-Haenszel test stratified by pooled site. Time-to-first-event comparisons were performed using Kaplan-Meier analysis, and p values were generated using adjusted log-rank test stratified by treatment group. Cumulative days at clinical and patient-reported responses (percentage of the maximum area-under-the-curve times study duration) were compared by ANCOVA.Of the 1027 patients randomly assigned, 90% completed the trial (465/520 ixekizumab and 459/507 guselkumab). As early as Week 2 and through Week 16, more patients on ixekizumab achieved PASI 100 (p<0·01). At Week 24, ixekizumab was non-inferior to guselkumab (50% vs. 52%, difference: -2·3%), with no statistically significant difference in PASI 100 (p=0·414). More patients receiving ixekizumab showed completely clear nails at Week 24 (52% vs. 31%; p=0·007). The median time-to-first PASI 50/75/90 and PASI 100 were 2 and 7.5 weeks shorter, respectively, for patients on ixekizumab versus guselkumab (p<0·001). Patients on ixekizumab also had a greater cumulative benefit, with more days at PASI 90 and 100, Dermatology Life Quality Index of 0 or 1, and itch-free (p<0·05). Serious adverse event frequency was 3% for each group with no new safety signals.Ixekizumab was non-inferior to guselkumab in complete skin clearance and superior in clearing nails at Week 24. Ixekizumab cleared skin more rapidly in patients with moderate-to-severe plaque psoriasis, with a greater cumulative benefit, than guselkumab. Overall, safety findings were consistent with the known safety profile for ixekizumab.