ΔNp63α is a nuclear transcription factor that maintains epithelial progenitor cell populations, is overexpressed in several epithelial cancers, and can negatively regulate apoptosis. However, the mechanisms by which ΔNp63α promotes cell survival are unclear. ΔNp63α has been reported to act as a transcriptional repressor, but specific target genes directly repressed by ΔNp63α remain unidentified. Here, we present evidence that ΔNp63α functions to negatively regulate the proapoptotic protein IGFBP-3. Disruption of p63 expression in squamous epithelial cells increases IGFBP-3 expression, whereas ectopic expression of ΔNp63α down-regulates IGFBP-3. ΔNp63α binds to sites in the IGFBP-3 gene in vivo and can modulate transcription through these sites. Furthermore, ΔNp63α and IGFBP-3 expression patterns are inversely correlated in normal squamous epithelium and squamous cell carcinomas. These data suggest that IGFBP-3 is a target of transcriptional repression by ΔNp63α and that this repression represents a mechanism by which tumors that overexpress p63 may be protected from apoptosis.