Significance p53 is the most frequently mutated, well-studied tumor-suppressor gene, yet the switch from p53-induced cell-cycle arrest to apoptosis remains poorly understood. We unexpectedly identify a critical role for the only human pseudo-caspase FLIP(L) in regulating this switch. Genetically or pharmacologically inhibiting expression of FLIP(L), which we identify as a new p53 transcriptional target, promoted apoptosis over cell-cycle arrest in response to p53 activation. Mechanistically, FLIP(L) inhibited p53-induced apoptosis by blocking ligand-independent activation of caspase-8 by the TRAIL-R2/DR5 death receptor. Notably, FLIP(L) also modulated transcription of canonical p53 target genes: increasing expression of cell-cycle regulator p21 and suppressing upregulation of apoptosis-inducing PUMA. Thus, we report unexpected, therapeutically exploitable roles for FLIP(L) in regulating the switch from p53-induced cell-cycle arrest to apoptosis.