Central pain syndrome (CPS) is a debilitating condition that affects a large number of patients with a primary lesion or dysfunction in the CNS. Despite its discovery over a century ago, the pathophysiological processes underlying the development and maintenance of CPS are poorly understood. We recently demonstrated that activity in the posterior thalamus (PO) is tightly regulated by inhibitory inputs from zona incerta (ZI). Here we test the hypothesis that CPS is associated with abnormal inhibitory regulation of PO by ZI. We recorded single units from ZI and PO in animals with CPS resulting from spinal cord lesions. Consistent with our hypothesis, the spontaneous firing rate and somatosensory evoked responses of ZI neurons were lower in lesioned animals compared with sham-operated controls. In PO, neurons recorded from lesioned rats exhibited significantly higher spontaneous firing rates and greater responses to noxious and innocuous stimuli applied to the hindpaw and to the face. These changes were not associated with increased afferent drive from the spinal trigeminal nucleus or changes in the ventroposterior thalamus. Thus CPS can result from suppressed inputs from the inhibitory nucleus zona incerta to the posterior thalamus.