The tumor suppressor p53 plays a crucial role in maintaining the genetic integrity of the cell and in suppressing cell transformation. Its cellular levels are usually low and rise substantially in response to DNA damage. Although research on p53 induction following DNA damage has mainly focused on the post-translational modification of p53 by Mdm2, it is known that protein translation also contributes to p53 induction. However, the mechanisms underlying translational regulation of the p53 protein in response to DNA damage are still poorly understood. We show that p53 synthesis increases dramatically in MCF-7 cells treated with etoposide. Interestingly, this increase is accompanied by an increase in the association of the translation initiation factor eIF-4E with its binding protein 4E-BP1, an inhibitor of cap-dependent protein translation. We further identified an internal ribosomal entry site (IRES) located in the 5′-untranslated region of the p53 transcript, that is capable of driving the cap-independent translation of a downstream cistron encoding Firefly luciferase in a dicistronic expression vector. Moreover, we found that the activity of the IRES element increases in response to etoposide-induced DNA damage in MCF-7 cells. These findings provide a novel mechanism for the regulation of p53 translation in response to DNA damage.