Tildrakizumab is an anti-interleukin-23p19 monoclonal antibody approved to treat moderate to severe plaque psoriasis. This study evaluated the efficacy and safety of tildrakizumab in patients with ankylosing spondylitis (AS). In this randomized, double-blind, parallel-group, multinational trial (clinicaltrials.gov NCT02980705), patients with active AS, according to modified New York criteria and Bath Ankylosing Spondylitis Disease Activity Index Score ≥4, were randomized 1:1 to tildrakizumab 200 mg or placebo every 4 weeks until week 24. Thereafter, all patients received tildrakizumab 200 mg every 4 weeks until week 48. The primary outcome was proportion of patients achieving 20% improvement from baseline by Assessment in SpondyloArthritis International Society criteria (ASAS20) at week 24. This outcome was analyzed in subgroups defined by prior treatment experience, weight, age, and sex using the full analysis set. Safety was assessed through treatment-emergent adverse events. From December 5, 2017-September 3, 2019, 101 patients (76.2% male, 97% White) enrolled and were randomized to treatment. At week 24, the ASAS20 response rate was 74.0% in patients receiving tildrakizumab 200 mg (n = 50) versus 80.4% in placebo-treated patients (n = 51; treatment difference, -6.31%; 95% confidence interval, -22.34 to 9.71; p = 0.44). No difference in treatment effect by subgroups was observed. Tildrakizumab treatment was generally well tolerated, with no unexpected safety findings. The study was terminated after the week 24 interim analysis due to lack of efficacy. Tildrakizumab treatment was generally well tolerated but did not improve ASAS20 response rate versus placebo in patients with AS.