Multisensory neurons in the SC integrate within-modal cues quite differently from cross-modal cues; rather than additivity or superadditivity, simultaneous presentation of excitatory stimuli from the same modality typically yields a response that is subadditive (Alvarado et al., 2007). That the same SC neuron can integrate excitatory influences differently depending on their source is fortuitous from a functional perspective, however, details of the neural architecture underlying this dual capacity is not clear. A likely candidate is the projection to the SC from regions of the anterior ectosylvian cortex (AES) which has been shown to be necessary for promoting the additive and superadditive interactions typical of multisensory enhancement (Wallace and Stein, 1994; Jiang et al., 2001). The present study examines the degree to which the AES-derived cortico-collicular projection is multisensory-specific by evaluating the impact of cortical inactivation on both unisensory and multisensory integration in the same multisensory neurons. We found that cortical inactivation nearly abolished multisensory enhancement but had no impact on unisensory integration in the very same neurons. These findings suggest that this cortico-collicular circuit has evolved expressly for the purpose of combining information across multiple senses and, in doing so, highlight an essential distinction between within-modal and cross-modal processing architectures.