Electrical low-frequency stimulation (LFS) of spinal afferents induces long-term depression (LTD) of nociceptive processing in rodents. LTD and its parameters in man are largely unknown. This study addresses the hypothesis that LTD of spinal nociception and pain in man depends on LFS frequency (0.5, 1, 2 Hz), number of electrical pulses (300, 600, 1200), intensity (relating to pain threshold I(P): 1 x I(P), 2 x I(P), 4 x I(P)), and on LFS repetition. One hundred and twenty electrophysiological and psychophysical experiments were performed in 29 healthy volunteers. Painful electrical test stimulation (0.125 Hz) and conditioning LFS were applied to right hand dorsum by a concentric electrode. Somatosensory evoked cortical potentials (SEP) were recorded and volunteers rated stimulus intensity. LFS with 0.5, 1, and 2 Hz induced significant reduction of SEP and pain ratings as compared to Control group. Effect on SEP amplitude after 1 Hz LFS preponderated that of 2 Hz stimulation. LTD of SEP and pain perception was induced by noxious LFS with 300-1200 pulses. SEP suppression augmented with increasing number of pulses. LFS with intensities 2 x I(P) and 4 x I(P) evoked sustained depression of SEP and pain perception in comparison to Control and 1 x I(P) LFS. Established LTD after single LFS was amplified by an additional second LFS. Hence this study provides electrophysiological and psychophysical evidence for LTD of spinal nociceptive processing and pain perception in man and indicates appropriate LFS parameters 1 Hz, 1200 pulses and 4 x I(P) for future studies on human LTD.