Losartan is an oral antihypertensive agent that is rapidly metabolized to EXP3174 (angiotensin-subtype-1-receptor-blocker) and EXP3179 (peroxisome-proliferator-activated-receptor-gamma [PPARγ] agonist), which was shown in animal studies to reduce inflammation, enhance mitochondrial energetics, and improve muscle repair and physical performance. We conducted an exploratory pilot study evaluating losartan treatment in prefrail older adults (age 70-90 years, N=25). Participants were randomized to control (placebo) or treatment (daily oral losartan beginning at 25 mg per day and increasing every eight weeks) for a total of 6 months. Fatigue, hyperkalemia, and hypotension were the most observed side effects of losartan treatment. Participants in the losartan group had an estimated 89% lower odds of frailty (95% CI: 18% to 99% lower odds, p=0.03), with a 0.3-point lower frailty score than the placebo group (95% CI: 0.01 to 0.5 lower, p=0.04). Frailty score was also negatively associated with serum losartan and EXP3179 concentrations. For every one standard deviation increase in EXP3179 (i.e., 0.0011 ng/μL, based on sample values above detection limit) and EXP3174 (i.e., 0.27 ng/μL, based on sample values above detection limit ), there was a 0.0035 N (95% CI: 0.0019 to 0.0051, p<0.001) and a 0.0027 N (95% CI: 0.00054 to 0.0043, p=0.007) increase in average knee strength, respectively.© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.