Background: This paper describes the rationale and design of the ENVIS-ion Study, which aims to determine whether low-dose aspirin reduces the development of white matter hyper-intense (WMH) lesions and silent brain infarction (SBI). Additional aims include determining whether a) changes in retinal vascular imaging (RVI) parameters parallel changes in brain magnetic resonance imaging (MRI); b) changes in RVI parameters are observed with aspirin therapy; c) baseline cognitive function correlates with MRI and RVI parameters; d) changes in cognitive function correlate with changes in brain MRI and RVI and e) whether factors such as age, gender or blood pressure influence the above associations.Methods/Design: Double-blind, placebo-controlled trial of three years duration set in two Australian academic medical centre outpatient clinics. This study will enrol 600 adults aged 70 years and over with normal cognitive function and without overt cardiovascular disease. Subjects will undergo cognitive testing, brain MRI and RVI at baseline and after 3 years of study treatment. All subjects will be recruited from a 19,000-patient clinical outcome trial conducted in Australia and the United States that will evaluate the effects of aspirin in maintaining disability-free longevity over 5 years. The intervention will be aspirin 100 mg daily versus matching placebo, randomized on a 1:1 basis.Discussion: This study will improve understanding of the mechanisms at the level of brain and vascular structure that underlie the effects of aspirin on cognitive function. Given the limited access and high cost of MRI, RVI may prove useful as a tool for the identification of individuals at high risk for the development of cerebrovascular disease and cognitive decline.Trial Registration: clinicaltrials.gov Identifier: NCT01038583.