Studies purporting to show changes in brain structure following the popular, eight-week Mindfulness-Based Stress Reduction (MBSR) course are widely referenced despite major methodological limitations. Here, we present findings from a large, combined dataset of two, three-arm randomized controlled trials with active and waitlist (WL) control groups. Meditation-naive participants (n=218) completed structural MRI scans during two visits: baseline and post-intervention period. After baseline, participants were randomly assigned to WL (n=70), an 8-week MBSR program (n=75), or a validated, matched active control (n=73). We assessed changes in gray matter volume, gray matter density, and cortical thickness. In the largest and most rigorously controlled study to date, we failed to replicate prior findings and found no evidence that MBSR produced neuroplastic changes compared to either control group, at either the whole-brain level or in regions of interest drawn from prior MBSR studies.