A new method is proposed to reveal apparent evolutionary relationships between protein fragments with similar 3D structures by finding “intermediate” sequences in the proteomic database. Instead of looking for homologies and intermediates for a whole protein domain, we build a chain of intermediate short sequences, which allows one to link similar structural modules of proteins belonging to the same or different families. Several such chains of intermediates can be combined into an evolutionary tree of structural protein modules. All calculations were made for protein fragments of 20 aa residues. Three evolutionary trees for different module structures are described. The aim of the paper is to introduce the new method and to demonstrate its potential for protein structural predictions. The approach also opens new perspectives for protein evolution studies. Proteins 2007. © 2007 Wiley-Liss, Inc.