© The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. Background: This subgroup analysis of the Lifestyle Intervention and Independence for Elders trial evaluates the impact of a long-term physical activity (PA) intervention on rates of major mobility disability (MMD) among older adults according to their antihypertensive medication use. Methods: Lifestyle Intervention and Independence for Elders study participants were randomized to center-based PA or health education for a median of 2.7 years. Participants were sedentary men and women aged 70-89 years with objectively measured physical limitations. This analysis evaluated rates of MMD and persistent MMD among 1, 633 participants, according to antihypertensive medication use. Participants were designated as either (i) an angiotensin-converting enzyme (ACE) inhibitor user (ACEi+), (ii) a user of other antihypertensives not including ACEi (ACEi-), or (iii) nonusers of antihypertensive medications (AHT-). Interactions were explored between antihypertensive use and randomized arm. Results: Interaction terms for MMD (p=.214) and persistent MMD (p=.180) did not reach statistical significance. For MMD, PA displayed marginal effects among ACEi+(hazard ratio [HR]=0.76; 95%confidence interval [CI]=0.57, 1.02) and ACEi- (HR=0.76; 95%CI=0.60, 0.97) but not AHT- (HR=1.19; 95%CI=0.75, 1.87). For persistent MMD, the effect of PA was greatest among ACEi+(HR=0.57; 95%CI=0.39, 0.84) when compared to ACEi- (HR=0.76; 95%CI=0.55, 1.06) or AHT- (HR=1.18; 95%CI=0.59, 2.36). Conclusions: The effects of long-term PA on the incidence of MMD and persistent MMD were similar among three subgroups of older adults stratified by their antihypertensive medication use. However, though statistical interactions did not reach significance, several findings may warrant future study in other cohorts given the post hoc nature of this study.