We have investigated the interaction between the expression of p21 WAF1/CIP1/SDI1 , a stoichiometric inhibitor of Cdk, and the transcriptional activity of the oestrogen receptor a (ERa). Transient transfection experiments demonstrated that the expression of p21 WAF1/CIP1/SDI1 amplified the transcriptional activation by ERa. A dominant negative mutant of Cdk2 also enhanced the ERa transcriptional activity, indicating that the underlying mechanism relies on the inhibition of Cdk2 activity and cell cycle arrest. In agreement with this conclusion, experiments with p21 WAF1/CIP1/SDI1 mutants demonstrated that the domain involved in the binding of p21 WAF1/CIP1/SDI1 to Cdks was indispensable for the modulation of ERa activity. In addition, we show that expression of p21 WAF1/CIP1/SDI1 alleviates the block on CBP function mediated by Cdk2 and in turn stimulates transcriptional activation by ERa in a CBPhistone acetyltransferase (HAT)-dependent manner. These results suggest a novel mechanism by which p21 WAF1/CIP1/SDI1 functions as an enhancer of ERa activity through the modulation of CBP function.