Electrical high-frequency stimulation (HFS) of cutaneous afferents elicits an LTP-like increase of pain sensitivity in humans. In this study we compared the magnitude and time courses of the homotopic and heterotopic forms of pain long-term potentiation tested by electrical and mechanical stimulation, respectively. HFS in healthy subjects (n=73) elicited a significant pain increase in the stimulated area (homotopic pain LTP) and adjacent skin (heterotopic pain LTP) to 145% and 190% of control area, respectively (p<0.001) of similar time courses (half lives with a median of 6.9 and 4.9 h, respectively, p=0.45) suggesting early LTP (LTP1). None of the measures used to characterize the responses (magnitude, half life, time to full recovery) showed a significant correlation between homotopic and heterotopic LTP (range of correlation coefficients: -0.19 - +0.21, all n.s.). However, when tested by the same test stimuli (electrical), homotopic and heterotopic LTP were highly correlated (r = 0.91, p < 0.001). Notably, LTP half lives or decay times were independent of the initial response magnitude (r = 0.29 and 0.31, n.s.). These data suggest that homotopic and heterotopic LTP share a similar time course of early LTP independent of the test method. When tested by the same test stimuli homotopic and heterotopic LTP were highly correlated suggesting that pain LTP is governed by heterosynaptic mechanisms regardless of the test site. The independence of LTP magnitude and duration suggests independent mechanisms for induction and maintenance of human pain LTP. Supported by Deutsche Forschungsgemeinschaft FOR926 – grant Ma1251/9-1