OBJECTIVES: Examine the effect of aerobic exercise on structural brain age and explore potential mediators. METHODS: In a single-blind, 12-month randomized clinical trial, 130 healthy participants aged 26-58 years were randomized into a moderator-to-vigorous intensity aerobic exercise group or a usual-care control group. The exercise group attended 2 supervised 60-minute sessions per week in a laboratory setting plus home-based exercise to achieve 150 minutes of exercise per week. Brain-predicted age difference (brain-PAD) and cardiorespiratory fitness (CRF) were assessed at baseline and 12 months. Intention-to-treat (ITT) and completers analyses were performed. RESULTS: The 130 participants (67.7% female) had a mean (SD) age of 41.28 (9.93) years. At baseline, higher CRF (VO CONCLUSION: Engaging in 12 months of moderate-to-vigorous exercise reduced brain-PAD in early-to-midlife adults. The pathways by which these effects occur remain unknown.