Protein structure refinement aims to perform a set of operations given a predicted structure to improve model quality and accuracy with respect to the native in a blind fashion. Despite the numerous computational approaches to the protein refinement problem reported in the previous three CASPs, an overwhelming majority of methods degrade models rather than improve them. We initially developed a method tested using blind predictions during CASP10 which was officially ranked in 5th place among all methods in the refinement category. Here, we present Princeton_TIGRESS, which when benchmarked on all CASP 7,8,9, and 10 refinement targets, simultaneously increased GDT_TS 76% of the time with an average improvement of 0.83 GDT_TS points per structure. The method was additionally benchmarked on models produced by top performing three-dimensional structure prediction servers during CASP10. The robustness of the Princeton_TIGRESS protocol was also tested for different random seeds. We make the Princeton_TIGRESS refinement protocol freely available as a web server at http://atlas.princeton.edu/refinement. Using this protocol, one can consistently refine a prediction to help bridge the gap between a predicted structure and the actual native structure. Proteins 2014; 82:794–814. © 2013 Wiley Periodicals, Inc.