Evaluation of protein models against the native structure is essential for the development and benchmarking of protein structure prediction methods. Although a number of evaluation scores have been proposed to date, many aspects of model assessment still lack desired robustness. In this study we present CAD-score, a new evaluation function quantifying differences between physical contacts in a model and the reference structure. The new score uses the concept of residue–residue contact area difference (CAD) introduced by Abagyan and Totrov (J Mol Biol 1997; 268:678–685). Contact areas, the underlying basis of the score, are derived using the Voronoi tessellation of protein structure. The newly introduced CAD-score is a continuous function, confined within fixed limits, free of any arbitrary thresholds or parameters. The built-in logic for treatment of missing residues allows consistent ranking of models of any degree of completeness. We tested CAD-score on a large set of diverse models and compared it to GDT-TS, a widely accepted measure of model accuracy. Similarly to GDT-TS, CAD-score showed a robust performance on single-domain proteins, but displayed a stronger preference for physically more realistic models. Unlike GDT-TS, the new score revealed a balanced assessment of domain rearrangement, removing the necessity for different treatment of single-domain, multi-domain, and multi-subunit structures. Moreover, CAD-score makes it possible to assess the accuracy of inter-domain or inter-subunit interfaces directly. In addition, the approach offers an alternative to the superposition-based model clustering. The CAD-score implementation is available both as a web server and a standalone software package at http://www.ibt.lt/bioinformatics/cad-score/. Proteins 2013. © 2012 Wiley Periodicals, Inc.