Abstract: We explored the relationships between the use of Angiotensin II receptor blockers (ARBs), Angiotensin I-converting enzyme (ACE) genetic polymorphisms and memory performance in older adults, whilst controlling for confounders. Retrospective observational case-control study. 104 patients over 60 years of age (mean age 74) without known cognitive disorder were included, 52 cases (ARB users) and 52 controls (non-users). ACE insertion/deletion (ACE I/D) polymorphism was determined in all patients. The Wechsler Memory Scale (memory quotient) was used to evaluate cognition. We measured years of education, Charlson Comorbidity Index (CCI) and total number of medications taken. The mean (SD) age in cases and controls were: 75.3 (7.5) and 72.0 (7.0) respectively (p = 0.020). Cases had higher CCI (p = 0.006) and took more medications (p < 0.001). Cases had a higher memory quotient: 99.6 (5.9) and 95.3 (6.7) (p < 0.001). In the I/I group, cases had higher memory quotient [99.5 (5.5) vs. 95.0 (5.7), p = 0.005]. No significant difference in memory performance was found between cases and controls within genotype ACE I/D (p = 0.056) and D/D (p = 0.290). A multiple linear regression predicting memory score in n = 104 (predictors: ARB use, age, female sex, years of education, CCI, number of medications, ACE I/I status, interaction ARB user ACE I/I status) suggested that only ARB use (p = 0.001) and higher education (p < 0.001) were significant predictors of higher memory performance. Despite ARB users being older and more comorbid, their memory was better even when controlling for the ACE I/I risk genotype. Education may confer cognitive reserve. The protective role of ARBs merits further investigation.