Electrical low-frequency stimulation (LFS) of spinal afferents induces long-term depression (LTD) of nociceptive processing in rodents. Little is known about LTD and its stimulation conditions in human experiments. We tested different stimulation parameters in order to obtain the most effective design in man. Electrophysio- logical and psychophysical experiments were performed in 29 healthy subjects. Painful electrical test (0.125 Hz) and condition- ing stimuli (LFS: 0.5, 1, or 2 Hz; 300, 600, or 1200 pulses; 1x, 2x, or 4x IP; IP=pain threshold) were applied to the right hand dorsum by a concentric electrode. Somatosensory evoked cortical vertex potentials (SEP) were recorded via EEG. Volunteers gave stimu-lus intensity ratings (0 to 100). LFS is able to inhibit pain and nociception for at least one hour in man. Inhibitory effects of LFS depend on stimulus frequency, number of pulses and stimulation intensity. Stimulation protocol with 1 Hz, 1200 pulses and 4x IP induced the strongest sustained reduction of SEP and pain rating (-47.1% SEP, -43.8% Pain, p<0.001). Established LTD after single LFS was amplified (-54.6% SEP, -47.7% Pain, p<0.01) by a sec-ond LFS. Extent of LTD-effects corresponded to results in ro-dents. Existence of LTD and its amplification by repetitive LFS may qualify this approach for neuromodulatory treatment of pain.