Genital psoriasis affects 33-63% patients with psoriasis during the course of disease, usually leading to a severe reduction of patient’s quality of life. This study aims to retrospectively asses the effectiveness of interleukin (IL)-23 and IL-17 inhibitors in a real-life population affected by moderate-to-severe plaque psoriasis with genital involvement coming from our dermatology department. A total of 86 patients with diagnosis of moderate-to-severe plaque psoriasis with severe genital involvement were enrolled. Patient characteristics, Psoriasis Area and Severity Index (PASI), and Static Physician Global Assessment of Genitalia (sPGA-G) at each visit were recorded. During the treatment, the mean PASI decreased from 12,8 at 0,63 at week 52; PGA of 0/1 was reached by 97,40% at week 52 and by 100% of patients (37/37) at week 104. No significant differences between the IL-23 and IL-17 inhibitors were observed; indeed the bio-naive group of patients demonstrated superior response compared to the group of patient bio-experienced. Our findings confirmed that IL-23 and IL-17 inhibitors as a safe and effective therapeutic option for the treatment of genital psoriasis.