Cutaneous stimulation with CO2 laser pulses activates A delta of nociceptive afferents and evokes late cerebral potentials (LEPs), the amplitude of which correlates parametrically with the perceived magnitude estimation of laser pulses. Capsaicin is known to desensitize the nociceptive terminals of C fibers. In this double-blind, vehicle-controlled experiment, we tested the hypothesis that topical capsaicin would inactivate A delta afferents and lead to an attenuation of the LEPs. Subjects applied capsaicin cream to the dorsum of one hand and vehicle cream to the other 3 times daily for a period of 5 weeks. At weekly intervals before starting, during administration and after discontinuation of capsaicin, LEPs were recorded and psychophysical thresholds and magnitude estimation for several sensory modalities were determined. The results of this study showed that topical capsaicin significantly and reversibly decreased the magnitude estimation of suprathreshold heat pain, laser pulses and amplitude of the LEPs. There was no statistically significant difference in light touch, deep pain and mechanical pain detection thresholds between the capsaicin- and vehicle-treated hands. It indicated that topical capsaicin caused a definite functional and reversible inactivation of A delta nociceptive afferent transmission. The decline in the magnitude estimation of laser pulses concomitantly with the attenuation of LEP amplitudes supports the hypothesis that some A delta afferents mediate noxious heat in humans. These findings demonstrate the usefulness of LEP in the physiological evaluation of nociceptive pathways and its potential usefulness in objectively documenting the effect of pharmacological treatment on pain perception.