High-frequency electrical stimulation (HFS) elicits long-term potentiation-like enhancement of pain perception (pain-LTP) in human subjects (Klein et al. J Neurosci 2004). Animal models suggest that electrical low frequency stimulation (LFS) may reverse nociceptive LTP (depotentiation). Here we studied the effect of LFS on established pain-LTP in humans. Pain-LTP was induced by HFS (5x1s trains of 100Hz at 10s intervals) applied to forearm skin in 46 healthy subjects through an array of 48 punctate electrodes. LFS (1000 pulses at 1 Hz) was applied to the same site either once (n=24; 60 minutes after HFS) or three times (n=11; @ 60, 90, and 120 minutes after HFS) at 10x detection threshold. LFS at detection threshold served as control (n=7). Perceptual changes at the site of conditioning stimulation were tested by electrical test stimuli at 10x detection threshold via the conditioning electrode. After HFS, pain perception to electrical stimuli increased to 195% (potentiation; p<<0.0001). LFS led to a significant decrease of pain-LTP by 29% (depotentiation; p<0.002). Repetition of LFS led to further stepwise depotentiation. In contrast, LFS at detection threshold had no significant effect (p=0.46). Conspicuously, pain intensity of LFS (on average 12/100 NRS) was closely correlated with the degree of depotentiation (r= -0.67), and low pain ratings (!) elicited the most prominent depotentiation. In conclusion, pain-LTP following HFS can be reversed by repetitive moderately painful LFS suggesting depotentiation. This is most prominent at low levels of perceived pain reminiscent of just painful low-frequency TENS. Supported by Deutsche Forschungsgemeinschaft (FOR926- grant Ma1251/9-1)