Several studies show that transcription coactivators are often bi-functional ribonucleoprotein complexes that also regulate pre-mRNA processing and splicing decisions. Using sensitive sequence profile searches and structural comparisons we show that the C-terminal domain of the human coactivator protein ASC-1 defines a novel superfamily, the ASC-1 homology (ASCH) domain. The approximately 110 amino acid long ASCH domains are widely represented in all the three superkingdoms of life and several prokaryotic viruses. We show that the ASCH superfamily adopts a beta-barrel fold similar to the PUA domain superfamily. Using multiple lines of evidence, we suggest that members of the ASCH superfamily are likely to function as RNA-binding domains in contexts related to coactivation, RNA-processing and possibly prokaryotic translation regulation. Structural analysis of ASCH domains reveals the presence of a potential RNA-binding cleft associated with a conserved sequence motif, which is characteristic of this superfamily. Despite their similar structure, the ASCH and PUA domains appear to occupy distinct functional niches, with the former domains typically occurring in a standalone form in polypeptides, and the latter domains showing fusions to a variety of RNA-modifying enzymes.