This chapter examines the skin manifestations of adult-onset immunodeficiencies, a heterogeneous group of disorders characterized by impaired immune system function. It categorizes these conditions into antibody deficiencies, lymphocyte defects, immune dysregulation syndromes, and innate immune deficiencies, with a focus on their dermatological and systemic implications. Skin findings range from therapy-resistant infections, such as warts and candidiasis, to autoimmune conditions like eczema and vitiligo. The chapter discusses diagnostic approaches, including laboratory assessments and genetic testing, to identify underlying immune defects. Management strategies emphasize the importance of addressing recurrent infections and associated hematological conditions, such as lymphomas and myelodysplastic syndromes. This chapter highlights the diagnostic significance of dermatological symptoms as early indicators of immunodeficiency in adults.