Dietary restriction (DR) has multiple beneficial effects, the two most prominently studied being an increased longevity and an increased cancer protection. Mammalian Sirt1 is a protein deacetylase that has been linked to DR. To explore the relation between Sirt1 and DR, we have examined here DR-induced cancer protection in mice overexpressing Sirt1 (2-3 fold) under its own regulatory elements (Sirt1-tg mice). In particular, we have subjected p53‑deficient mice, carrying or not the Sirt1-tg allele, to every-other-day fasting (EOD), which is a type of DR that significantly delays cancer onset. As expected, EOD extended the survival of p53-heterozygous (p53 (+/-) ) mice. However, the extension of survival of p53-heterozygous mice by EOD was the same in the presence or absence of the Sirt1-tg allele. These results suggest that Sirt1 has a limited role in mediating cancer protection by DR in mammals.