Background Determining the disulfide (S-S) bond pattern in a protein is often crucial for understanding its structure and function. In recent research, mass spectrometry (MS) based analysis has been applied to this problem following protein digestion under both partial reduction and non-reduction conditions. However, this paradigm still awaits solutions to certain algorithmic problems fundamental amongst which is the efficient matching of an exponentially growing set of putative S-S bonded structural alternatives to the large amounts of experimental spectrometric data. Current methods circumvent this challenge primarily through simplifications, such as by assuming only the occurrence of certain ion-types (b-ions and y-ions) that predominate in the more popular dissociation methods, such as collision-induced dissociation (CID). Unfortunately, this can adversely impact the quality of results. Method We present an algorithmic approach to this problem that can, with high computational efficiency, analyze multiple ions types (a, b, bo, b*, c, x, y, yo, y*, and z) and deal with complex bonding topologies, such as inter/intra bonding involving more than two peptides. The proposed approach combines an approximation algorithm-based search formulation with data driven parameter estimation. This formulation considers only those regions of the search space where the correct solution resides with a high likelihood. Putative disulfide bonds thus obtained are finally combined in a globally consistent pattern to yield the overall disulfide bonding topology of the molecule. Additionally, each bond is associated with a confidence score, which aids in interpretation and assimilation of the results. Results The method was tested on nine different eukaryotic Glycosyltransferases possessing disulfide bonding topologies of varying complexity. Its performance was found to be characterized by high efficiency (in terms of time and the fraction of search space considered), sensitivity, specificity, and accuracy. The method was also compared with other techniques at the state-of-the-art. It was found to perform as well or better than the competing techniques. An implementation is available at: http://tintin.sfsu.edu/~whemurad/disulfidebond. Conclusions This research addresses some of the significant challenges in MS-based disulfide bond determination. To the best of our knowledge, this is the first algorithmic work that can consider multiple ion types in this problem setting while simultaneously ensuring polynomial time complexity and high accuracy of results.