MOTIVATION: Global protein surface comparison (GPSC) studies have been limited compared to other research works on protein structure alignment/comparison due to lack of real applications associated with GPSC. However, the technology advances in cryo-electron tomography (CET) have made methods to identify proteins from their surface shapes extremely useful. RESULTS: In this study, we developed a new method called Farthest point sampling (FPS)-enhanced Triangulation-based Iterative-closest-Point (ICP) (FTIP) for GPSC. We applied it to protein classification using only surface shape information. Our method first extracts a set of feature points from protein surfaces using FPS and then uses a triangulation-based efficient ICP algorithm to align the feature points of the two proteins to be compared. Tested on a benchmark dataset with 2329 proteins using nearest-neighbor classification, FTIP outperformed the state-of-the-art method for GPSC based on 3D Zernike descriptors. Using real and simulated cryo-EM data, we show that FTIP could be applied in the future to address problems in protein identification in CET experiments. AVAILABILITY AND IMPLEMENTATION: Programs/scripts we developed/used in the study are available at http://ani.stat.fsu.edu/∼yuan/index.fld/FTIP.tar.bz2. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.