NF-kappaB is a pleiotropic transcription factor involved in multiple processes, including inflammation and oncogenesis. We have previously reported that COMMD1 represses kappaB-dependent transcription by negatively regulating NF-kappaB-chromatin interactions. Recently, ubiquitination of NF-kappaB subunits has been similarly implicated in the control of NF-kappaB recruitment to chromatin. We report here that COMMD1 accelerates the ubiquitination and degradation of NF-kappaB subunits through its interaction with a multimeric ubiquitin ligase containing Elongins B and C, Cul2 and SOCS1 (ECS(SOCS1)). COMMD1-deficient cells demonstrate stabilization of RelA, greater nuclear accumulation of RelA after TNF stimulation, de-repression of several kappaB-responsive genes, and enhanced NF-kappaB-mediated cellular responses. COMMD1 binds to Cul2 in a stimulus-dependent manner and serves to facilitate substrate binding to the ligase by stabilizing the interaction between SOCS1 and RelA. Our data uncover that ubiquitination and degradation of NF-kappaB subunits by this COMMD1-containing ubiquitin ligase is a novel and critical mechanism of regulation of NF-kappaB-mediated transcription.