AbstractPYRIN domains were identified recently as putative protein–protein interaction domains at the N‐termini of several proteins thought to function in apoptotic and inflammatory signaling pathways. The ∼95 residue PYRIN domains have no statistically significant sequence homology to proteins with known three‐dimensional structure. Using secondary structure prediction and potential‐based fold recognition methods, however, the PYRIN domain is predicted to be a member of the six‐helix bundle death domain‐fold superfamily that includes death domains (DDs), death effector domains (DEDs), and caspase recruitment domains (CARDs). Members of the death domain‐fold superfamily are well established mediators of protein–protein interactions found in many proteins involved in apoptosis and inflammation, indicating further that the PYRIN domains serve a similar function. An homology model of the PYRIN domain of CARD7/DEFCAP/NAC/NALP1, a member of the Apaf‐1/Ced‐4 family of proteins, was constructed using the three‐dimensional structures of the FADD and p75 neurotrophin receptor DDs, and of the Apaf‐1 and caspase‐9 CARDs, as templates. Validation of the model using a variety of computational techniques indicates that the fold prediction is consistent with the sequence. Comparison of a circular dichroism spectrum of the PYRIN domain of CARD7/DEFCAP/NAC/NALP1 with spectra of several proteins known to adopt the death domain‐fold provides experimental support for the structure prediction.