BACKGROUND: TFIID is a multiprotein complex that plays a pivotal role in the regulation of RNA polymerase II (Pol II) transcription owing to its core promoter recognition and co-activator functions. TAF6 is a core TFIID subunit whose splice variants include the major TAF6alpha isoform that is ubiquitously expressed, and the inducible TAF6delta. In contrast to TAF6alpha, TAF6delta is a pro-apoptotic isoform with a 10 amino acid deletion in its histone fold domain that abolishes its interaction with TAF9. TAF6delta expression can dictate life versus death decisions of human cells. RESULTS: Here we define the impact of endogenous TAF6delta expression on the global transcriptome landscape. TAF6delta was found to orchestrate a transcription profile that included statistically significant enrichment of genes of apoptotic function. Interestingly, gene expression patterns controlled by TAF6delta share similarities with, but are not equivalent to, those reported to change following TAF9 and/or TAF9b depletion. Finally, because TAF6delta regulates certain p53 target genes, we tested and demonstrated a physical and functional interaction between TAF6delta and p53. CONCLUSION: Together our data define a TAF6delta-driven apoptotic gene expression program and show crosstalk between the p53 and TAF6delta pathways.