© 2015, Public Library of Science. All rights reserved. Objective: To identify early changes in brain structure and function that are associated with cardiovascular risk factors (CVRF). Design: Cross-sectional brain Magnetic Resonance I (MRI) study. Setting: Community based cohort in three U.S. sites. Participants: A Caucasian and African-American sub-sample (n= 680; mean age 50.3 yrs) attending the 25 year follow-up exam of the Coronary Artery Risk Development in Young Adults Study. Primary and Secondary Outcomes: 3T brain MR images processed for quantitative estimates of: total brain (TBV) and abnormal white matter (AWM) volume; white matter fractional anisotropy (WM-FA); and gray matter cerebral blood flow (GM-CBF). Total intracranial volume is TBV plus cerebral spinal fluid (TICV). A Global Cognitive Function (GCF) score was derived from tests of speed, memory and executive function. Results: Adjusting for TICV and demographic factors, current smoking was significantly associated with lower GM-CBF and TBV, and more AWM (all <0.05); SA with lower GM-CBF, WM-FA and TBV (p=0.01); increasing BMI with decreasing GM-CBF (p<0003); hypertension with lower GM-CBF, WM-FA, and TBV and higher AWM (all <0.05); and diabetes with lower TBV (p=0.007). The GCS was lower as TBV decreased, AWM increased, and WM-FA (all p<0.01). Conclusion: In middle age adults, CVRF are associated with brain health, reflected in MRI measures of structure and perfusion, and cognitive functioning. These findings suggest markers of midlife cardiovascular and brain health should be considered as indication for early intervention and future risk of late-life cerebrovascular disease and dementia.