Atopic dermatitis (AD) out-of-pocket (OOP) expenses are substantial and impact household finances. Prescription polypharmacy and its association with OOP expenses in AD is poorly understood.To characterize prescription polypharmacy and its association with OOP healthcare expenses among individuals with AD.An online survey was administered to National Eczema Association members (N=113,502). Inclusion criteria (US resident, age ≥18, self-reported or caregiver of individual with AD) was met by 77.3% (1,118/1,447) of respondents.Polypharmacy (≥5 prescription treatments for AD in the past year) was associated with increased AD severity, poorer control, increased flares, increased healthcare provider visits, and comorbid asthma, allergic rhinitis, food allergy, and skin infections (P≤0.01). Polypharmacy noted with all prescription therapies was most associated with biologic (dupilumab), oral immunosuppressant (azathioprine, cyclosporine, methotrexate, corticosteroids), oral antimicrobial, and topical calcineurin inhibitor (P≤0.0005) use. Respondents with polypharmacy had increased OOP expenditures across numerous categories, including office visit co-pays, prescription medications both covered and not covered by insurance, hospitalization, emergency room visits, mental health services, non-prescription health products such as sleep aids, analgesics, and supplements, and alternative medications (P<0.005). Individuals with polypharmacy had elevated yearly OOP expenses (median [range]: $1200 [$0-$200,000]), higher monthly OOP costs than average, and more harmful household financial impact (P<0.0001 for all).Individuals with AD report considerable polypharmacy, which is associated with increased OOP expenses and harmful financial impact. Strategies are needed to reduce polypharmacy, minimize OOP costs, and optimize clinical outcomes. J Drugs Dermatol. 2023;22(2): doi:10.36849/JDD.7038.