The nuclear factor‐kappaB (NF‐κB) transcription factor system is a crucial component that controls several important biological functions, thus raising the need for mechanisms that ensure the correct termination of its activity. Here, we identify a new phosphorylation/ubiquitination switch in the NF‐κB network that controls the stability of the transactivating p65 subunit. Tumour necrosis factor‐induced phosphorylation of p65 at Ser468 allows binding of COMMD1 and cullin 2, components of a multimeric ubiquitin ligase complex mediating p65 ubiquitination. Mutation of p65 at Ser468 largely prevents p65 ubiquitination and proteasomal degradation. Inducible p65 elimination is restricted to a subset of NF‐κB target genes such as Icam1. Accordingly, chromatin immunoprecipitation experiments reveal the selective recruitment of Ser468‐phosphorylated p65 and COMMD1 to the Icam1 promoter. Phosphorylation of p65 at Ser468 leads to ubiquitin/proteasome‐dependent removal of chromatin‐bound p65, thus contributing to the selective termination of NF‐κB‐dependent gene expression.