The glucocorticoid receptor (GR) is a ligand-dependent transcription factor which regulates growth, development and metabolic functions. To test the hypothesis that the pleiotropic effect of the GR could be mediated by other transcription factors/oncogenes, the present study assessed its interaction with the tumor suppressor p53. p53 is a transcription factor which is involved in cell cycle regulation and apoptosis. We found that the wild-type p53 physically interacted with the GR and repressed the glucocorticoid-dependent transcriptional activity. In contrast, mutant p53 had no or a lesser effect depending on the type of p53 mutant. These findings raised the possibility that p53 may play an important role in modulating the activities of glucocorticoids in cells.