Using the yeast two-hybrid system, we isolated a human cDNA that encodes a protein (hp22) interacting with TATA box-binding factor TFIID subunit p80 containing similarity with histone H4. Sequence analysis showed that the open reading frame (ORF) specifies a 161-amino-acid (aa) polypeptide homologous to Drosophila melanogaster TFIID subunit p22 (dp22). Comparison of the aa sequence of human TFIID subunit p22 (hp22) with that of dp22 revealed that p22 is composed of two distinct regions; the less conserved N-terminal (20% identity) and the highly conserved C-terminal (65% identity) regions. Additionally, the C-terminal region was found to contain similarities with histones H2B and H3. Northern blot analysis showed mRNA corresponding to hp22 to be expressed in all tissues examined.