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Background: Evidence exists that lowering high blood pressure reduces the risk of dementia. However, the generalizability of this evidence to old patients from the general population remains uncertain., Objectives: This study sought to evaluate the effect of antihypertensive drug treatment on the risk of dementia in a heterogeneous group of new users of antihypertensive drugs., Methods: A nested case-control study was carried out by including the cohort of 215,547 patients from Lombardy, Italy, aged ≥65 years, who started taking antihypertensive drugs between 2009 and 2012. Cases were the 13,812 patients (age 77.5 ± 6.6 years; 40% men) who developed dementia or Alzheimer's disease during follow-up (up to 2019). For each case, 5 control subjects were selected to be matched for sex, age, and clinical status. Exposure to drug therapy was measured by the proportion of the follow-up covered by antihypertensive drugs. Conditional logistic regression was used to model the outcome risk associated with exposure to antihypertensive drugs., Results: Exposure to treatment was inversely associated with the risk of dementia. Compared with patients with very low exposure, those with low, intermediate, and high exposure exhibited a 2% (95% CI: -4% to 7%), 12% (95% CI: 6%-17%), and 24% (95% CI: 19%-28%) risk reduction, respectively. This was also the case for very old (aged ≥85 years) and frail patients (ie, those characterized by a high mortality risk at 1 year)., Conclusions: In the old fraction of the general population, antihypertensive drug treatment is associated with a lower risk of dementia. This was also the case in very old and frail patients., Competing Interests: Funding Support and Author Disclosures This study was supported by a grant from the Italian Ministry of Health (Ricerca Finalizzata 2016, NET-2016-02363853). The funding source had no role in the design of the study, the collection, analysis and interpretation of the data, or the decision to approve publication of the finished manuscript. Dr Corrao has received research support from the European Community, the Italian Medicines Agency, the Italian Ministry of Health, and the Italian Ministry of Education, University, and Research; has participated in various projects that were funded by Novartis, GSK, Roche, Amgen, Bristol Myers Squibb, and Servier; and has received honoraria from Roche as a member of its advisory board. Dr Mancia has received honoraria for participation as speaker or chairman in national or international meetings from Bayer, Boehringer Ingelheim, CVRx, Daiichi-Sankyo, Ferrer, Medtronic, Menarini Int, Merck, Novartis, Recordati, and Servier. Dr Rea has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)