To investigate the effects of homotopic and heterotopic conditioning pain modulation (CPM) on short-term cortical plasticity. Glutamate (tonic pain) or isotonic saline (sham) was injected in the upper trapezius (homotopic) and in the thenar (heterotopic) muscles. Intramuscular electrical stimulation was applied to the trapezius at pain threshold intensities, and somatosensory evoked potentials were recorded with 128 channel EEG. Pain ratings were obtained during glutamate and sham pain injection. Short-term cortical plasticity to electrical stimulation was investigated before, during, and after homotopic and heterotopic CPM versus control. Peak latencies at N100, P200, and P300 were extracted and the location/strength of corresponding dipole current sources and multiple dipoles were estimated. Homotopic CPM caused hypoalgesia (P = 0.032, 30.6% compared to baseline) to electrical stimulation. No cortical changes were found for homotopic CPM. A positive correlation at P200 between electrical pain threshold after tonic pain and the z coordinate after tonic pain (P = 0.032) was found for homotopic CPM. For heterotopic CPM, no significant hypoalgesia was found and a dipole shift of the P300 z coordinate (P = 0.001) was found between glutamate versus sham pain (P = 0.009). This generator was located in the cingulate. A positive correlation at P300 between pain ratings to glutamate injection and the x coordinate during tonic pain (P = 0.016) was found for heterotopic CPM. Heterotopic CPM caused short-term cortical plasticity within the cingulate that was correlated to subjective pain ratings. The degree of long-term depressive effect to homotopic CPM was correlated to the change in location of the P200 dipole.