Tildrakizumab is an anti-interleukin-23 p19 monoclonal antibody approved for the treatment of adults with moderate-to-severe plaque psoriasis. Little real-world evidence is available regarding the effects of tildrakizumab on patients’ health-related quality of life (HRQoL) and patient-reported symptoms. This real-world study of tildrakizumab evaluated changes in HRQoL and clinical symptoms in patients with psoriasis. In this Week (W)28 interim analysis of a 64-week Phase 4 study (NCT03718299), patients received tildrakizumab 100 mg at W0, W4, and every 12 weeks thereafter. Endpoints were improvement from baseline in Psychological General Well-Being Index (PGWBI), Dermatology Life Quality Index (DLQI), and Itch-, Pain-, and Scaling-Numerical Rating Scale scores through W28. Of 55 patients enrolled, 53 were assessed at W28. Mean (standard deviation [SD]) total PGWBI score improved from baseline to W28 (change, 3.7 [12.4]; = .033), as did the positive well-being (1.0 [2.9]; = .018) and general health (1.5 [2.2]; <.001) domain scores. Mean (SD) DLQI score improved by -3.9 (4.3) at W4 and by -7.6 (5.1) at W28 ( <.001). Patient-reported symptoms improved starting at W4 ( <.001). Tildrakizumab treatment improved HRQoL and patient-reported symptoms in patients with psoriasis in a real-world setting.