The present study was aimed at evaluating the time-dependent expressions of phosphorylated forms in the cAMP/calcium response element binding protein (pCREB) known to be one of transcription factors for immediate early genes in the brain stem nuclei of Sprague-Dalwey rats. Animals received surgical ablation of right peripheral vestibular labyrinth through a ventral approach. Immunohistochemical staining and digital image analysis systems were used to observe pCREB expressions in neuronal cells of the brain stem nuclei. The number of pCREB labeling neurons were increased with time, and peaked in the vestibular nuclear complex (VNC) bilaterally 1 h after unilateral labyrinthectomy (UL). In addition, high levels of phosphorylated CREB-like immunoreactivity (pCREB-LI) were also observed in bilateral cerebellum, olivary nuclear complex, and medullary nuclei. There was a rapid reduction of pCREB-LI in contralateral VNC but a slow reduction in the ipsilateral side 2 h after UL, causing an asymmetric number of pCREB labeling neurons between bilateral VNC (P<0.05). Thereafter pCREB-LI in bilateral VNC decreased to a very low level and returned to basal level 24 h after UL. These results suggest that the activation of the cAMP/calcium response element binding protein plays a role in the initial events of vestibular compensation in rats.