Tandem mass spectrometry (MS/MS) experiments often generate redundant data sets containing multiple spectra of the same peptides. Clustering of MS/MS spectra takes advantage of this redundancy by identifying multiple spectra of the same peptide and replacing them with a single representative spectrum. Analyzing only representative spectra results in significant speed-up of MS/MS database searches. We present an efficient clustering approach for analyzing large MS/MS data sets (over 10 million spectra) with a capability to reduce the number of spectra submitted to further analysis by an order of magnitude. The MS/MS database search of clustered spectra results in fewer spurious hits to the database and increases number of peptide identifications as compared to regular nonclustered searches. Our open source software MS-Clustering is available for download at http://peptide.ucsd.edu or can be run online at http://proteomics.bioprojects.org/MassSpec.