High and low frequency repetitive transcranial magnetic stimulation (rTMS) are both used to treat major depressive disorder(MDD). However, the physiological mechanisms underlying the therapeutic benefit and the effect of the stimulation frequency are unclear. Twelve healthy participants received 1Hz, 2Hz, and 5Hz active rTMS. Twenty 5 second trains were delivered at left dorsolateral prefrontal cortex at 110 of resting motor threshold with a 25 second inter-train interval. Blood oxygenation (HbO) was significantly reduced following the 1Hz trains compared to the HbO increases observed in both the 2Hz and 5Hz conditions. There was no significant inter-hemispheric difference in response. These results suggest that short trains of high and low frequency rTMS delivered to prefrontal cortex evoke a differential HbO response and provide additional evidence that high frequency trains result in increased neural activity. The findings may provide further explanation for the improved symptoms observed in MDD patients treated with high frequency rTMS. ? 2013 Elsevier Inc. All rights reserved.