Fourth intracerebroventricular (4th-icv) administration of the melanocortin-3/4 receptor (MC3/4-R) agonist, MTII, reduces food intake; the antagonist, SHU9119, increases feeding. The dorsal motor nucleus of the vagus nerve (DMX) contains the highest density of MC4-R messenger RNA in the brain. To explore the possibility that the DMX contributes to 4th-icv MC4-R effects, we delivered doses of MTII and SHU9119 that are subthreshold for ventricular response unilaterally through a cannula centered above the DMX. MTII markedly suppressed 2-h (50%), 4-h (50%), and 24-h (33%) intake. Feeding was significantly increased 4 h (50%) and 24 h (20%) after SHU9119 injections. These results suggest that receptors in the DMX, or the dorsal vagal complex more generally, underlie effects obtained with 4th-icv administration of these ligands. We investigated possible vagal mediation of 4th-icv MTII effects by giving the agonist to rats with subdiaphragmatic vagotomy. MTII suppressed 2-, 4-, and 24-h liquid diet intake (∼80%) to the same extent in vagotomized and surgical control rats. We conclude that stimulation or antagonism of MC3/4-Rs in the dorsal vagal complex yields effects on food intake that do not require an intact vagus nerve.