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Introduction: Psoriasis affecting the genital, palmoplantar, and scalp regions is recognized as difficult-to-treat, and data on the efficacy of biologics in these areas remains limited., Research Design and Methods: This single-center study evaluated the effectiveness of anti-IL-17 and anti-IL-23 agents on scalp, genital, and palmoplantar psoriasis. We retrospectively analyzed data from all patients with psoriasis being treated with IL inhibitors at our clinic. Effectiveness was evaluated at 16, 28, and 52 weeks, according to the achievement of relative and mean PSSI, PGA-G, and ppPASI., Results: In all, 308 patients showed involvement of the scalp, 136 in the genital area, and 94 in the palmoplantar regions. On scalp psoriasis, anti-IL-17 agents demonstrated superiority in disease control compared to anti-IL-23 agents. PSSI100 at week 16 was reached by 59% of patients on an anti-IL17 vs 39.8% on an anti-IL-23 ( p  < 0.003). At genital sites, no significant differences between anti-IL-17 and anti-IL-23 agents were observed, and all classes achieved PGA-G 0/1. No significant differences between anti-IL-17 and anti-IL-23 agents were observed in palmoplantar areas., Conclusions: The present data support the utility of both anti-IL-17 and anti-IL-23 agents for the treatment of difficult-to-treat areas in patients with psoriasis. Anti-IL-17 agents achieved better control of scalp psoriasis.