Novel stimuli in all sensory modalities are highly effective in attracting and focusing attention. Stimulus-specific adaptation (SSA) and brain activity evoked by novel stimuli have been studied using population measures such as imaging and event-related potentials, but there have been few studies at the single-neuron level. In this study we compare SSA across different populations of neurons in the inferior colliculus (IC) of the rat and show that a subclass of neurons with rapid and pronounced SSA respond selectively to novel sounds. These neurons, located in the dorsal and external cortex of the IC, fail to respond to multiple repetitions of a sound but briefly recover their excitability when some stimulus parameter is changed. The finding of neurons that respond selectively to novel stimuli in the mammalian auditory midbrain suggests that they may contribute to a rapid subcortical pathway for directing attention and/or orienting responses to novel sounds.