Rostral ventrolateral medulla (rVLM) and parapyramidal region (PPr) serve as important medullary control sites for sympathoexcitation. rVLM and PPr have direct projections to the intermediolateral cell column (IML) that are thought to be important in maintaining mean arterial blood pressure (MAP). Substance P (SP) is found in PPr neurons and in and near the subretrofacial area of the rVLM. At least some of these cells project to the IML. We investigated the involvement of SP at the IML in mediating rVLM- and PPr-evoked pressor responses in the chloralose-anesthetized cat. Pressor responses to electrical and chemical PPr and rVLM stimulation were altered after intrathecal injection, at the level of the T1-T3 spinal cord, of either SP antagonist [D-Pro², D-Phe⁷, D-Trp⁹]-SP, SP antagonist CP 96,345, or SP antiserum. Although MAP and heart rate responses to PPr stimulation were attenuated by intrathecal SP antagonists or antiserum, MAP responses to rVLM stimulation were augmented. Previous studies have revealed differences in transmitters associated with these two areas, even though the general response of both areas is sympathoexcitatory. The present study implies that the identical substance may increase or decrease the MAP response depending on the pathway activated.