MDMA (3,4-methylenedioxymethamphetamine; Ecstasy) is a popular recreational drug that produces long-lasting serotonin (5-HT) neurotoxicity consisting of reductions in markers for 5-HT axons. 5-HT innervates cortical and subcortical brain regions mediating motor function, predicting that MDMA users will have altered motor system neurophysiology. We used functional magnetic resonance imaging (fMRI) to assay motor task performance-associated brain activation changes in MDMA and non-MDMA users. 24 subjects (14 MDMA users and 10 controls) performed an event-related motor tapping task (1, 2 or 4 taps) during fMRI at 3 T. Motor regions of interest were used to measure percent signal change (PSC) and percent activated voxels (PAV) in bilateral motor cortex, sensory cortex, supplementary motor area (SMA), caudate, putamen, pallidum and thalamus. We used SPM5 to measure brain activation via three methods: T-maps, PSC and PAV. There was no statistically significant difference in reaction time between the two groups. For the Tap 4 condition, MDMA users had more activation than controls in the right SMA for T-score (p=0.02), PSC (p=0.04) and PAV (p=0.03). Lifetime episodes of MDMA use were positively correlated with PSC for the Tap 4 condition on the right for putamen and pallidum; with PAV in the right motor and sensory cortex and bilateral thalamus. In conclusion, we found a group difference in the right SMA and positive dose-response association between lifetime exposure to MDMA and signal magnitude and extent in several brain regions. This evidence is consistent with MDMA-induced alterations in basal ganglia-thalamocortical circuit neurophysiology and is potentially secondary to neurotoxic effects on 5-HT signaling. Further studies examining behavioral correlates and the specific neurophysiological basis of the observed findings are warranted.