Amide bond protonation triggering peptide fragmentations and the controversial b -ion structures have both been subjects of intense research. The involvement of histidine (H), with its imidazole side-chain which induces specific dissociation patterns involving inter-side-chain (ISC) interactions, on b -ion formation was investigated, focusing on the QHS model tripeptide.To pinpoint the effect of histidine on fragmentations issued from ISC interactions, QHS was selected for a comprehensive analysis of the pathways leading to the three possible b -ion structures, using quantum chemical calculations performed at the DFT/B3LYP/6-311+G* level of theory. In addition, electrospray ionization ion trap mass spectrometry allowed recording MS and MS tandem mass spectra, while the Quantum Chemical Mass Spectrometry for Materials Science (QCMS ) method was used as tool to predict fragmentation patterns.Whereas it is probably very difficult to unambiguously differentiate between protonated oxazolone, diketopiperazine or lactam b -ions from MS and MS mass spectra alone, the calculations indicated that the QH b -ion (detected at m/z 266) is probably a mixture of the lactam and oxazolone structures formed after amide nitrogen protonation, making the diketopiperazine form less likely to occur as it requires an additional step in its formation.In contrast to glycine-histidine-containing b -ions known to be issued from backbone-imidazole cyclization, we found that interactions between the side chains were not that obvious to perceive, neither from a thermodynamics nor from a fragmentation perspective, emphasizing the importance of the whole sequence on the dissociation behavior usually demonstrated from simple glycine-containing tripeptides.