The Sixth Community Wide Experiment on the Critical Assessment of Techniques for Protein Structure Prediction (CASP6) held in December 2004 focused on the prediction of the structures of 90 protein domains from 64 targets. Thirty-eight of these were classified as “fold recognition,” defined as being similar in fold to proteins of known structure at the time of submission of the predictions. Only the “first” predictions and those longer than 20 amino acids for each domain were assessed, resulting in 4527 predictions from 165 groups. The assessment was accomplished by the use of six structure alignment programs and three scoring measures based on these alignments. The use of a variety of measures resulted in scoring insensitive to the peculiarities of any one alignment method. The top-ranked methods in the prediction of structures that were clearly homologous to proteins in the Protein Data Bank primarily used servers and other programs based on achieving a consensus of many remote homology detection and fold recognition methods. The top-ranked methods in prediction of structures less clearly related or unrelated to proteins of known structures used fragment building methods in addition to the fold recognition meta methods. Proteins 2005;Suppl 7:46–66. © 2005 Wiley-Liss, Inc.