The anterior pretectal nucleus has recently been implicated in the descending modulation of nociception. Electrical stimulation of the nucleus was found to reduce the nociceptive responses of deep dorsal horn neurons and to inhibit spinally integrated withdrawal reflexes. It is believed that at least part of the descending inhibitory effects of the anterior pretectal nucleus are mediated by reticulospinal cells of the ventrolateral medulla. The purpose of the present study was to trace the direct medullary projections of the anterior pretectal nucleus, to describe their topographical organization and to reveal the chemical nature of some of their putative target cells. The connections were studied using anterograde tract-tracing with Phaseolus vulgaris leucoagglutinin. Direct projections from the anterior pretectal nucleus to the ipsilateral rostral ventral medulla were found in all cases. A dense innervation of the dorsal inferior olive, the gigantocellular reticular nucleus pars ventralis and pars alpha and the ventral pontine reticular nucleus was found from all aspects of the anterior pretectal nucleus. Descending labelled terminals were also observed in the gigantocellular reticular nucleus proper and, laterally, in the lateral paragigantocellular nucleus and in the region of the A5 noradrenergic cell group. A relatively lower density of labelled terminals was noted in the medullary raphe nuclei and in the rostroventrolateral reticular nucleus. Following tract-tracer injections into five distinct subregions of the anterior pretectal nucleus, the topographical organization of the projection was examined and the relatively highest density and most widespread projection was found to originate from the caudoventral part of the anterior pretectal nucleus. A combined tract-tracing and immunolabelling study revealed that some of the descending, labelled terminals were in close proximity of tyrosine hydroxylase-immunoreactive dendrites in the C1 and A5 cell groups. Some labelled fibres were also noted among the serotonin-immunoreactive cells in the lateral extension of the B3 cell population. The existence of direct projections to the ventral medulla and pons correlates well with physiological data which showed that the descending, antinociceptive effects of the anterior pretectal nucleus are relayed via the rostral ventrolateral medulla. The data are also in keeping with pharmacological studies that suggested the role of catecholaminergic cells in the mediation of these descending effects. It is proposed that the rostral ventral medullary projections provide a path through which antinociceptive effects of the anterior pretectal nucleus are mediated to the spinal cord.