The efficacy of guselkumab has been demonstrated in randomized controlled trials, but real-life data are still missing. This study presents a single-center real-life experience in treating moderate-to-severe plaque psoriasis with guselkumab, underlying the efficacy and safety of this biological agent. Primary efficacy endpoint was the percentage of patients reaching psoriasis area and severity index (PASI) 90 response at week 28. The cohort included 79 patients of mean age 51 ± 15 years. Mean duration of guselkumab treatment was 16,5 ± 7.5 months. All 79 patients completed at least 28 weeks of treatment. At week 28, 73 (92%) patients reached PASI 50 or higher, 65 (82%) achieved PASI 75 or higher, 54 (68%) achieved PASI 90 or higher, and 35 (44%) reached PASI 100. Very similar percentages were found at week 44 and at the end of the study period. No significant adverse effects were reported. This study confirms that guselkumab is an effective and safe biologic agent capable of maintaining long-lasting clinical response efficacy in real-world clinical practice, although at slightly lower levels than in clinical trials. J Drugs Dermatol. 2022;21(8):864-866. doi:10.36849/JDD.6962.