Electrical peripheral nerve neurostimulation (PNS) is reported to be an effective pain treatment. An objective proof of antinociceptive effect is lacking. The human experimental study addressed PNS effects on nociception and pain by electrophysiology and psychophysics. In 23 healthy volunteers, 39 sessions were conducted. Three experiments (PNS ipsilateral, PNS contralateral, Control) consisted of 13 sessions each. Conditioning PNS (100 Hz) of left (PNS ipsilateral) or right (PNS contralateral) superficial radial nerve trunk evoked non-painful, tingling sensations on the hand dorsum. Local cutaneous anesthesia at PNS site provided for preferential nerve trunk stimulation. Cortical laser-evoked potentials (LEP) after painful stimulation at left hand dorsum were recorded together with mechanical and thermal perception thresholds at the same site before (T1), during (T2), and after (T3) PNS or a no stimulation period (Control). Mechanical and thermal perception decreased in the anesthetized area. Late LEP amplitude decreased independently of PNS site. Exclusively under ipsilateral PNS, N2 latency increased and laser ratings decreased. Mechanical detection threshold transiently increased during ipsilateral PNS at hand dorsum. PNS induced strong reduction of mechanical perception due to peripheral collision of orthodromic (test stimulus) and antidromic (PNS) selective Abeta fiber excitation. Delay of N2 component and reduction of laser pain were specific to ipsilateral PNS. Divergent and common effects of ipsilateral and contralateral PNS suggest a combination of peripheral and central antinociceptive mechanisms. The study in man documents inhibition of nociception and pain by PNS and provides with an experimental model for future objectives in neuromodulation.