Abstract The present study determined whether the effects of peripherally administered substance P on memory are mediated via activation of the vagus nerve. Rats were submitted to subdiaphragmatic vagotomy, sham vagotomy or non-operated, and trained in a step-down inhibitory avoidance task and tested 24 h later. Posttraining administration of 50 μg/kg of SP facilitated retention performance in non-operated and sham-operated groups. The facilitating effects of 50 μg/kg of SP was blocked by vagotomy, although vagotomy did not attenuate the memory-enhancing effects of larger doses (250 and 500 μg/kg). These results suggest that the mnemotropic effects of peripherally administered SP are sensitive to the functional integrity of the vagus nerve. Alternatively, the vagus nerve may be one pathway but not the only pathway by which systemic SP influences the memory storage processes in the brain.