Clinical trials have demonstrated the efficacy and safety of guselkumab in patients with moderate-to-severe plaque psoriasis. Real-world evidence for guselkumab in Korea is needed to establish drug safety and effectiveness under real-world practice in this population. This study assessed the effectiveness, safety, and drug survival of guselkumab in Korean patients with moderate-to-severe plaque psoriasis in a real-world clinical setting. In this prospective, non-interventional observational study conducted at 44 clinical centers in South Korea, adult patients with moderate-to-severe plaque psoriasis who would receive guselkumab per the product label were enrolled. Disease assessment was performed at visits 1 (baseline, week 0), 2 (approximately week 4), and 3-7 (approximately every 8 weeks after week 4, weeks 12-44). Between February 25, 2019 and March 25, 2022, 707 patients were enrolled and 562 (79.5%) had completed the 56-week observation period. The proportions of patients with an absolute Psoriasis Area and Severity Index (PASI) score of ≤ 3, ≤ 2, or ≤ 1 reached maximums of 96.0%, 86.7%, and 59.0%, respectively, at visit 7. A significantly greater proportion of biologic-naïve (vs. biologic-experienced) patients achieved absolute PASI ≤ 3 by visits 5-7 (p = 0.001 at visit 7) and absolute PASI ≤ 2 by visits 6-7 (p = 0.0014 at visit 7). Dermatology Life Quality Index (DLQI) scores decreased over time, with 64.1% of patients achieving DLQI 0/1 by visit 7; results were similar regardless of prior biologic therapy. The estimated drug-survival rate at 1 year was 92.7%. Adverse events (AEs) occurred in 22.5% of patients, with an incidence rate of 42.1 per 100 patient years (PY); 14 serious AEs occurred in 13 (1.8%) patients, with an incidence rate (95% confidence interval) of 2.4 (1.2-3.7) per 100 PY. Guselkumab administered under approved label conditions was effective and well-tolerated in Korean patients with moderate-to-severe plaque psoriasis in a real-world clinical setting.