Transcriptional repression by the C-terminal binding protein (CtBP) is proposed to require nicotinamide adenine dinucleotide dehydrogenase (NAD(H). Previous studies have implicated CtBP in transcriptional repression of the p21 waf1/cip1 gene. Similarly, the NAD-dependent poly(adenosine diphosphate)ribose polymerase 1 (PARP1) may affect p21 expression via its NAD-dependent enzymatic activity; we therefore asked if PARP1 and CtBP were functionally linked in regulating p21 transcription. We found that restraint of basal p21 transcription requires both CtBP and PARP1. PARP inhibition attenuated activation of p21 transcription by both p53-independent and p53-dependent processes, in a CtBP-dependent manner. CtBP12 or PARP12 knockdown partially activated p21 gene expression, suggesting relief of a corepressor function dependent on both proteins. We localized CtBP-responsive repression elements to the proximal promoter region, and found ZBRK1 overexpression could also overcome DNA damage-dependent, but not p53-dependent activation through this region. By chromatin immunoprecipitation we find dismissal of CtBP from the proximal promoter following DNA-damage, and that PARP1 associates with a CtBP corepressor complex in nuclear extracts. We propose a model in which both CtBP and PARP functionally interact in a corepressor complex as components of a molecular switch necessary for p21 repression, and following DNA damage signals activation of p21 transcription by corepressor dismissal and co-activator recruitment.