Low frequency stimulation (LFS) of spinal afferents induces long-term depression (LTD) of nociception in rodents. The present study demonstrates and characterizes LTD of nociceptive processing in man. Electrophysiological and psychophysical experiments were performed in 41 healthy volunteers (24 female, 17 male; 25.8±4.4 years). Painful electrical test (0.125 Hz) and conditioning stimuli (LFS: 1200 pulses at 0.5, 1, or 2 Hz) were applied to the right hand dorsum by a concentric electrode. Somatosensory evoked cortical vertex potentials (SEP) were recorded via EEG. Volunteers gave test stimulus intensity ratings (0 to 100). Within one hour after 1 Hz-LFS, SEP amplitude significantly decreased as compared to baseline (-45.5%; p<0.001) and to control experiments (p<0.01). Inhibitory effects of LFS did not depend on stimulus frequency (0.5, 1, 2 Hz). Established LTD after single LFS (-44.2%; p<0.001), was amplified to -60.1% by an additional second LFS (p<0.01). Ratings equally decreased. LTD of nociceptive processing from the hand was demonstrated in man. Extent of inhibitory effects and LFS frequency corresponded to results in rodents. Existence of LTD and its amplification by repetitive LFS may qualify this approach for neuromodulatory treatment of pain.