Pain is a complex experience involving extensive interactions between brain and spinal cord processes. Various interventions that modulate pain, such as the application of a competing noxious stimulus (counterirritation), are thought to involve cerebrospinal regulation through diffuse noxious inhibitory controls (DNICs). However, no study has yet examined the relation between brain and spinal cord activity during counterirritation analgesia in humans. This fMRI study investigates brain responses to phasic painful electrical stimulation administered to the sural nerve to evoke a spinal nociceptive response (RIII reflex) before, during and after counterirritation induced by the immersion of the left contralateral foot in cold water. Responses are compared with a control condition without counterirritation. As expected, counterirritation produced robust pain inhibition with residual analgesia persisting during the recovery period. In contrast, RIII reflex amplitude was significantly decreased by counterirritation only in a subset of subjects. Modulatory effects of counterirritation on pain perception and spinal nociception were paralleled by decreased shock-evoked activity in pain-related areas. Individual changes in shock-evoked brain activity were specifically related to analgesia in primary somatosensory cortex (SI), anterior cingulate cortex and amygdala, and to RIII modulation in supplementary motor area and orbitofrontal cortex (OFC). Moreover, sustained activation induced by the counterirritation stimulus in the OFC predicted shock-pain decrease while sustained activity in SI and the periaqueductal gray matter predicted RIII modulation. These results provide evidence for the implication of at least two partly separable neural mechanisms underlying the effects of counterirritation on pain and spinal nociception in humans.