Extracellular recordings of 125 neurons in the rostroventral medulla (RVM) were performed in 35 rats that were maintained in a light plane of anesthesia with methohexital. The neurons were classified as ON, OFF, or NEUTRAL cells, depending on their response to noxious heat applied to the tail. ON cells showed an increase in firing rate just before the tail flick (TF). OFF cells showed a decrease in firing rate just before the TF, and NEUTRAL cells showed no correlation between neural activity and the TF. The effects of electrical stimulation of cervical vagal afferents (VAS) on 1) the activity of ON, OFF, and NEUTRAL cells, 2) TF latency, and 3) arterial blood pressure (ABP) were determined at intensities less than or equal to the intensity of VAS necessary to inhibit the TF reflex to a cutoff latency of 10 s. VAS excited 70.8% of the ON cells and inhibited 77.8% of the OFF cells at greater intensities, including intensities that inhibited the TF. However, 55.6% of the OFF cells inhibited by the threshold intensity of VAS to inhibit the TF reflex were excited by lesser intensities of VAS (<50% of the intensity that inhibited the TF) that facilitated the TF reflex, and 14.3% of the ON cells excited by the threshold intensity of VAS to inhibit the TF reflex were inhibited by lesser intensities of VAS. VAS had mixed effects on NEUTRAL cells. VAS excited 23.7% and inhibited 10.5% of the NEUTRAL cells that had somatic receptive fields. VAS excited 12.9% and inhibited 9.7% of the NEUTRAL cells that had no identified somatic receptive field. The excitation of ON cells and inhibition of OFF cells produced by VAS at the intensity to inhibit the TF are opposite to predicted outcomes on the basis of current theories on the function of ON and OFF cells in nociception. VAS produced a depressor response at intensities ranging from ~50% to 100% of the VAS intensity necessary to inhibit the TF reflex to the cutoff latency. At lesser intensities, VAS occasionally produced a small pressor response. ON and OFF cells generally showed marked fluctuations in background activity, shifting between active and inactive states. The levels of background neural activity were correlated with mean ABP. ABP levels were lower when ON cells were active and OFF cells were inactive than when ON cells were inactive and OFF cells active. In addition, during heat control trials, ABP decreased at the time of the TF, which corresponds to a time when ON cells are active and OFF cells are inactive. Further, VAS at intensities that excited ON cells and inhibited OFF cells generally produced a depressor response. These data suggest that ON and OFF cells in the RVM are involved in cardiovascular regulation. One possible interpretation of the present data is that VAS- induced alterations in ON and OFF cell activity are related to changes in nociception and/or ABP, but that if the neurons are important for VAS-induced antinociception, then ON and OFF cells cannot function in the modulation of nociception in the manner previously proposed.