<h3>Objective:</h3> To assess the skin irritation and sensitization potential of once-weekly 5-mg/d donepezil transdermal delivery system (TDS). <h3>Background:</h3> Once-weekly donepezil TDS (Adlarity®) was approved in 2022 by the US FDA for the treatment of mild, moderate, and severe dementia of the Alzheimer’s type. <h3>Design/Methods:</h3> In this placebo (vehicle), TDS-controlled, randomized, double-blind phase 1 trial (NCT03397862), healthy volunteers aged ≥40 years were evaluated for skin irritation and sensitization potential. Participants were randomized to receive weekly applications of 5-mg/d donepezil TDS on one side of the back and placebo TDS on the opposite side, or vice-versa, with 3 consecutive weekly TDS applications to the same skin site. During a challenge phase, donepezil TDS and placebo TDS were applied to naïve skin sites on opposite sides of the back in a randomized manner for 48 hours. Skin irritation scoring was performed weekly after TDS removal. <h3>Results:</h3> Among the 256 participants who received ≥1 dose of any treatment, the mean (SD) age was 54.3 years (9.4 years). After 3 weekly assessments of TDS, the average of the mean combined irritation score was 0.55 of a possible maximum 7 for donepezil TDS, indicating none-to-minimal skin irritation, and 0.19 for placebo TDS, indicating no skin irritation (treatment difference, −34 [95% CI, −0.43, −0.25]). There was a slight numerical trend of better skin tolerability in participants aged ≥65 versus <65 years. Of 198 participants, 4 (2.0%) were considered potentially sensitized to donepezil TDS, and 0 were potentially sensitized to placebo TDS. <h3>Conclusions:</h3> Once-weekly 5-mg/d donepezil TDS demonstrated acceptable skin tolerability, with minimal skin irritation under conditions of use of 3 consecutive weekly patch applications to the same skin site and minimal sensitization potential, supporting its use as treatment for dementia of the Alzheimer type. <b>Disclosure:</b> Dr. Sabbagh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Eisai. Dr. Sabbagh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genetech=Roche. Dr. Sabbagh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novo Nordisk. Dr. Sabbagh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lilly. Dr. Sabbagh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Synaptogenix. Dr. Sabbagh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Signant Health. Dr. Sabbagh has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for T3D. Dr. Sabbagh has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for EIP Pharma. Dr. Sabbagh has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Quince-Cortexyme. Dr. Sabbagh has stock in Neurotau. Dr. Sabbagh has stock in Seq Biomarque. Dr. Sabbagh has stock in uMethod Health. Dr. Sabbagh has stock in Athira. Dr. Sabbagh has stock in Lighthouse Pharmaceuticals. Dr. Sabbagh has stock in Alzheom. The institution of Dr. Sabbagh has received research support from NIH. The institution of Dr. Sabbagh has received research support from ADDF. Dr. Sabbagh has received publishing royalties from a publication relating to health care. Dr. MATHEW has nothing to disclose. Dr. Blau has received personal compensation for serving as an employee of Corium. Dr. Blau has stock in Johnson & Johnson.