Background: Phase II data suggested that guselkumab, an anti-interleukin-23 monoclonal antibody, was efficacious in psoriasis. Objective: We sought to assess efficacy and safety of guselkumab in moderate to severe psoriasis versus placebo and adalimumab, including interrupted treatment and switching adalimumab nonresponders to guselkumab. Methods: Patients were randomized to guselkumab 100 mg (weeks 0 and 4, then every 8 weeks; n = 496); placebo ->guselkumab (weeks 0, 4, and 12 then guselkumab at weeks 16 and 20; n = 248); or adalimumab (80 mg week 0, then 40 mg week 1, and every 2 weeks through week 23; n = 248). At week 28, guselkumab 90% or greater improvement in Psoriasis Area and Severity Index (PASI) score from baseline (PASI 90) responders were rerandomized to guselkumab or placebo with guselkumab after loss of response. Placebo ->guselkumab responders and adalimumab responders received placebo, then guselkumab after loss of response. Nonresponders received guselkumab. Results: At week 16, more patients receiving guselkumab achieved an Investigator Global Assessment (IGA) score 0/1 (cleared/minimal) (84.1% vs 8.5%) and PASI 90 (70.0% vs 2.4%) versus placebo (coprimary end points). Guselkumab was superior to adalimumab at week 16 (IGA score 0/1, 75% or greater improvement in PASI score from baseline, and PASI 90) and week 24 (IGA score 0/1 and 0, PASI 90, 100% improvement in PASI score from baseline) (P < .001). From weeks 28 to 48, better persistence of response was observed in guselkumab maintenance versus withdrawal groups (P < .001). Of adalimumab nonresponders who switched to guselkumab, 66.1% achieved PASI 90 at week 48. Guselkumab improved patient-reported outcomes. Adverse events were comparable among groups. Limitations: One-year follow-up limits retreatment data. Conclusions: Guselkumab is a highly effective, well-tolerated, maintenance therapy, including in adalimumab nonresponders.