AbstractHydrogen peroxide (H₂O₂)-based products are effective in tooth whitening; however, their safety is controversial as they may harm patient tissues/cells. These effects are suggested to be concentration-dependent; nonetheless, to date, there are no reports on H₂O₂-mediated oxidative damage in the gingival tissue, and neither whether this can be detected in gingival crevicular fluid (GCF) samples. We hypothesize that H₂O₂ whitening products may cause collateral oxidative tissue damage following in office application. Therefore, H₂O₂ and nitric oxide (NO) levels were investigated in GCF samples obtained from patients undergoing dental bleaching with H₂O₂ at different concentrations, in a randomized, double-blind, split-mouth clinical trial. A proteomic analysis of these samples was also performed. H₂O₂-based whitening products promoted inflammation which was detected in GCF samples and lasted for longer following 35% H₂O₂ bleaching. This included time-dependent changes in NO levels and in the abundance of proteins associated with NO synthesis, oxidative stress, neutrophil regulation, nucleic acid damage, cell survival and/or tissue regeneration. Overall, H₂O₂-based products used in office promote inflammation irrespective of their concentration. As the inflammation caused by 35% H₂O₂ is longer_, patients may benefit better from using lower concentrations of this bleaching product, as they may result in less tissue damage.