The identification of transcriptional targets of the tumor suppressor p53 is crucial in understanding mechanisms by which it affects cellular outcomes. Through expression array analysis, we identified cyclooxygenase 2 (Cox‐2), whose expression was inducible by wild‐type p53 and DNA damage. We also found that p53‐induced Cox‐2 expression results from p53‐mediated activation of the Ras/Raf/MAPK cascade, as demonstrated by suppression of Cox‐2 induction in response to p53 by dominant‐negative Ras or Raf1 mutants. Furthermore, heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF), a p53 downstream target gene, induced Cox‐2 expression, implying that Cox‐2 is an ultimate effector in the p53→ HB‐EGF→ Ras/Raf/MAPK→ Cox‐2 pathway. p53‐induced apoptosis was enhanced greatly in Cox‐2 knock‐out cells as compared with wild‐type cells, suggesting that Cox‐2 has an abrogating effect on p53‐induced apoptosis. Also, a selective Cox‐2 inhibitor, NS‐398, significantly enhanced genotoxic stress‐induced apoptosis in several types of p53+/+ normal human cells, through a caspase‐dependent pathway. Together, these results demonstrate that Cox‐2 is induced by p53‐mediated activation of the Ras/Raf/ERK cascade, counteracting p53‐mediated apoptosis. This anti‐apoptosis effect may be a mechanism to abate cellular stresses associated with p53 induction.