We demonstrate that ΔNp63α is an essential survival factor in head and neck squamous cell carcinoma (HNSCC) through its ability to suppress p73-dependent apoptosis. Inhibition of endogenous p63 expression by RNAi induces apoptosis selectively in HNSCC cells that overexpress ΔNp63α. Knockdown of p63 induces the proapoptotic bcl-2 family members Puma and Noxa, and both their induction and subsequent cell death are p53 independent but require transactivating isoforms of p73. Inhibition of p73-dependent transcription by ΔNp63α involves both direct promoter binding and physical interaction with p73. In HNSCC cells lacking endogenous ΔNp63α expression, bcl-2 is instead upregulated and can suppress p73-mediated death. Together, these data define a pathway whereby ΔNp63α promotes survival in squamous epithelial malignancy by repressing a p73-dependent proapoptotic transcriptional program.