Silent brain infarcts (SBIs) are detected by neuroimaging in approximately 20% of elderly patients in populationbased studies. Limited evidence is available for hypertensives at low cardiovascular risk countries. Investigating Silent Strokes in Hypertensives: A Magnetic Resonance Imaging Study (ISSYS) is aimed to assess the prevalence and risk factors of SBIs in a hypertensive Mediterranean population. This is a cohort study in randomly selected hypertensives, aged 50 to 70 years old, and free of clinical stroke and dementia. On baseline, all participants underwent a brain magnetic resonance imaging to assess prevalence and location of silent infarcts, and data on vascular risk factors, comorbidities, and the presence of subclinical cardiorenal damage (left ventricular hypertrophy and microalbuminuria) were collected. Multivariate analyses were performed to determine SBIs associated factors. A total of 976 patients (49.4% men, mean age 64 years) were enrolled, and 163 SBIs were detected in 99 participants (prevalence 10.1%; 95% CI, 8.4%-12.2%), most of them (64.4%) located in the basal ganglia and subcortical white matter. After adjustment, besides age and sex, microalbuminuria and increasing total cardiovascular risk (assessed by the Framingham-calibrated for Spanish population risk function) were independently associated with SBIs. Male sex increased the odds of having SBIs in 2.5 as compared with females. Our results highlight the importance of considering both global risk assessment and sex differences in hypertension and may be useful to design future preventive interventions of stroke and dementia. © 2014 American Heart Association, Inc.