Suppression of heat responses in primary nociceptive neurons when stimulated repeatedly was shown in animal models in vivo (fatigue of AP-discharges) and in vitro (tachyphylaxis of heat-induced currents). We now investigated whether heat pain in humans correspondingly display signs of habituation. Heat pain and evoked potentials (EP) were elicited in 16 volunteers with a contact heat evoked potential stimulator (CHEPS; Medoc, Israel). Three stimulus intensities were applied in random order (threshold, moderate and maximum available [51°C]) either to fixed or variable locations at the volar right forearm. The CHEPS reliably induced heat pain (e.g., numeric rating scale [NRS, 0–100]: 33.9 ± 6.9 at maximum temperature, variable location) and heat-evoked potentials. Pain ratings and EP-amplitudes (N2P2 component) displayed significant temperature dependence and were reduced when heat pulses were applied to a fixed skin area (p<0.005, respectively; main task effect, ANOVA) with the largest differences seen at the moderate noxious temperature (factor of about 2). These task differences clearly depended upon fatigue in the condition fixed stimulation where ratings and EPs markedly decreased during the first stimuli and then remained approximately constant. In conclusion human heat pain displays signs of habituation reflecting tachyphylaxis and fatigue of peripheral nociceptive neurons. Supported by DFG Tr236/11-3 and 13-3