The tumor suppressor protein p53 regulates transcription of many genes that mediate cell cycle arrest, apoptosis, DNA repair and other cellular responses. Here we show that Ipaf, a human CED-4 homologue and an activator of caspase-1, is induced by p53. Overexpression of p53 by transfection in U2OS and A549 cells increased Ipaf mRNA levels. Treatment of p53-positive cell lines U2OS and MCF-7 with the DNA damaging drug, doxorubicin, which increases p53 protein level, induced expression of Ipaf mRNA but similar treatment of MCF-7-mp53 (a clone of MCF-7 cells expressing mutant p53) and p53-negative K562 cells showed much less induction of Ipaf gene expression. Expression analysis for Ipaf mRNA in doxorubicin-treated human tumor cell lines suggests that p53-dependent as well as p53-independent mechanisms are involved in the regulation of Ipaf gene expression in a cell-type-specific manner. The Ipaf promoter was activated by normal p53 but not by His(273) mutant of p53. A functional p53-binding site was identified in the Ipaf promoter. A dominant-negative mutant of Ipaf inhibited p53-induced and doxorubicin-induced apoptosis by about 50%. Ipaf-directed small hairpin RNA downregulated p53-induced Ipaf gene expression and also reduced p53-induced apoptosis. Doxorubicin-induced apoptosis was also inhibited by Ipaf-directed small hairpin RNA. Our results show that p53 can directly induce Ipaf gene transcription, which contributes to p53-dependent apoptosis in at least some human cells.