In normal subjects, heterotopic painful stimuli induce simultaneous and parallel decreases in the sensation of pain and in the spinal nociceptive flexion (RIII) reflex evoked by electrical stimulation of the sural nerve. This inhibition of the RIII reflex is not seen in tetraplegic patients with clinically complete spinal cord transection, suggesting that supraspinal structures are involved in this type of inhibition, mediated through ‘Diffuse Noxious Inhibitory Controls’ (DNIC). In the present study, the effects of heterotopic nociceptive stimuli on the RIII reflex were examined in 3 patients with unilateral thalamic vascular lesions and in 3 with Wallenberg's syndrome (WS). In the former, as in normal subjects, nociceptive electrical conditioning stimuli applied to the analgesic hand produced a profound inhibition of the RIII reflex followed by long-lasting after-effects. No inhibition was observed in the WS patients. The same conditioning procedure applied to the nonanalgesic hand of the WS patients resulted inhibition and after-effects similar to those observed in normal subjects. The fact that noxious but nonpainful stimuli triggered DNIC in the patients with thalamic lesions excludes the possibility that masking of pain by a second painful focus is mainly due to attentional processes. It is also concluded that lemniscal and spinothalamic pathways are not involved in the triggering of DNIC in man and it is suggested that the brainstem and probably the spinoreticular tract are key neuronal links in the loop subserving DNIC in man.