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Background and objectives: Post stroke cognitive impairment (PSCI) is an understudied, long-term complication of stroke, impacting nearly 30-40% of all stroke survivors. No cure is available once the cognitive deterioration manifests. Compound 21 (C21), a novel selective non-peptide angiotensin receptor (AT2R) agonist, has also shown therapeutic efficacy in a variety of experimental stroke models, but C21 effect on PSCI model is lacking. To our knowledge, this is the first study to investigate the long-term effects of C21 treatment on the development of PSCI in aged animals.Methods: Distal docal cerebral ischemia was induced in 14-month-old male Wistar rats by direct electro-coagulation of middle cerebral artery for permanent occlusion (pMCAO). Animals were randomly assigned to receive either C21 or vehicle which was initiated the following day, and continued for a total of 30 days (0.12 mg/kg/d, orally). Outcome measures for sensorimotor and cognitive function were performed using a sequence of tests, all blindly conducted and assessed at baseline as well as at different time points post-pMCAO. Repeated measures ANOVA mixed models were used to examine differences in behavioral outcomes.Results: C21 reduced weight loss and enhanced recovery (Table). Treatment with C21 showed significant improvement in non-spatial and short-term working memory compared to vehicle. Moreover, C21 preserved reference memory and facilitated associative learning compared to vehicle treated rats after pMCAO. Further, C21 prevented Aβ1-42. C21 did not show any effect on motor deficits score compared to vehicle.Conclusion: Our findings demonstrate that the angiotensin receptor (AT2R) agonist C21 effectively preserves cognitive function and prevents the development of PSCI in aged animals.