Diverse molecular mechanisms have been discovered that mediate the loss of responses to the deprived eye during monocular deprivation. cAMP/Ca2+ response element-binding protein (CREB) function, in particular, is thought to be essential for ocular dominance plasticity during monocular deprivation. In contrast, we have very little information concerning the molecular mechanisms of recovery from the effects of monocular deprivation, even though this information is highly relevant for understanding cortical plasticity. To test the involvement of CREB activation in recovery of responses to the deprived eye, we used herpes simplex virus (HSV) to express in the primary visual cortex a dominant-negative form of CREB (HSV-mCREB) containing a single point mutation that prevents its activation. This mutant was used to suppress CREB function intracortically during the period when normal vision was restored in two protocols for recovery from monocular deprivation: reverse deprivation and binocular vision. In the reverse deprivation model, inhibition of CREB function prevented loss of responses to the newly deprived eye but did not prevent simultaneous recovery of responses to the previously deprived eye. Full recovery of cortical binocularity after restoration of binocular vision was similarly unaffected by HSV-mCREB treatment. The HSV-mCREB injections produced strong suppression of CREB function in the visual cortex, as ascertained by both DNA binding assays and immunoblot analysis showing a decrease in the expression of the transcription factor C/EBPbeta, which is regulated by CREB. These results show a mechanistic dichotomy between loss and recovery of neural function in visual cortex; CREB function is essential for loss but not for recovery of deprived eye responses.