The open (mass tolerant) search of tandem mass spectra of peptides shows great potential in the comprehensive detection of post-translational modifications (PTMs) in shotgun proteomics. However, this search strategy has not been widely used by the community, and one bottleneck of it is the lack of appropriate algorithms for automated and reliable post-processing of the coarse and error-prone search results. Here we present PTMiner, a software tool for confident filtering and localization of modifications (mass shifts) detected in an open search. After mass-shift-grouped false discovery rate (FDR) control of peptide-spectrum matches (PSMs), PTMiner uses an empirical Bayesian method to localize modifications through iterative learning of the prior probabilities of each type of modification occurring on different amino acids. The performance of PTMiner was evaluated on three data sets, including simulated data, chemically synthesized peptide library data and modified-peptide spiked-in proteome data. The results showed that PTMiner can effectively control the PSM FDR and accurately localize the modification sites. At 1% real false localization rate (FLR), PTMiner localized 93%, 84 and 83% of the modification sites in the three data sets, respectively, far higher than two open search engines we used and an extended version of the Ascore localization algorithm. We then used PTMiner to analyze a draft map of human proteome containing 25 million spectra from 30 tissues, and confidently identified over 1.7 million modified PSMs at 1% FDR and 1% FLR, which provided a system-wide view of both known and unknown PTMs in the human proteome.