Simple SummaryCutaneous manifestations were observed in ~44% of Iranian patients with monogenic IEI. A considerable number of these patients developed cutaneous disorders as their first manifestation of the disease. Skin disorders in IEI patients might delay the immunodeficiency diagnosis but may improve their prognosis.AbstractCutaneous manifestations are one of the most common presentations among patients with inborn errors of immunity (IEI). These skin manifestations are often among the first presenting features in the majority of patients preceding the IEI diagnosis. We studied 521 available monogenic patients with IEI listed in the Iranian IEI registry up to November 2022. We extracted each patient’s demographic information, detailed clinical history of cutaneous manifestations, and immunologic evaluations. The patients were then categorized and compared based on their phenotypical classifications provided by the International Union of Immunological Societies. Most patients were categorized into syndromic combined immunodeficiency (25.1%), non-syndromic combined immunodeficiency (24.4%), predominantly antibody deficiency (20.7%), and diseases of immune dysregulation (20.5%). In total, 227 patients developed skin manifestations at a median (IQR) age of 2.0 (0.5–5.2) years; a total of 66 (40.7%) of these patients initially presented with these manifestations. Patients with cutaneous involvement were generally older at the time of diagnosis [5.0 (1.6–8.0) vs. 3.0 (1.0–7.0) years;p= 0.022]. Consanguinity was more common among patients who developed skin disorders (81.4% vs. 65.2%,p< 0.001). The overall skin infection rate and the type of dominant pathogens were significantly different among the IEI patients in different phenotypical classifications (p< 0.001). Atopic presentation, including urticaria, was highly prevalent among patients with congenital defects of phagocytes (p= 0.020). The frequency of eczema was also significantly higher among cases with both syndromic and non-syndromic combined immunodeficiency (p= 0.009). In contrast, autoimmune cutaneous manifestations, including alopecia and psoriasis, were most common in patients with immune dysregulation (p= 0.001) and defects in intrinsic or innate immunity (p= 0.031), respectively. The presence of autoimmune cutaneous complications significantly improved the survival rate of IEI patients (p= 0.21). In conclusion, cutaneous manifestations were observed in nearly 44% of Iranian patients with monogenic IEI. A considerable number of patients with cutaneous involvements developed these disorders as their first manifestation of the disease, which was particularly noticeable in patients with non-syndromic combined immunodeficiency and phagocytic defects. The neglected skin disorders in IEI patients might delay diagnosis, which is generally established within a 3-year interval from the development of skin-related problems. Cutaneous disorders, especially autoimmune features, might indicate a mild prognosis in IEI patients.