Aim of the study To evaluate differences in the cellular expression of DNA damage/repair and reactive oxygen/nitrogen species between human periodontitis and peri‐implantitis lesions. Material and methods 40 patients presenting with generalized severe periodontitis and 40 patients with severe peri‐implantitis were included. Soft tissue biopsies were collected from diseased sites in conjunction with surgical therapy and prepared for histological analysis. Four regions of interest were identified: the pocket epithelium (PE), the infiltrated connective tissue (ICT), which was divided into one inner area facing the PE (ICT‐1) and one outer area (ICT‐2). A non‐infiltrated connective tissue area (NCT) lateral of the ICT was also selected. Results It was demonstrated that the ICT of peri‐implantitis specimens was considerably larger and contained significantly larger area proportions and densities of CD68‐, MPO‐ and iNOS‐positive cells than that of periodontitis samples. Cellular densities were overall higher in the inner ICT zone lateral of the PE (ICT‐1) than in the outer ICT compartment (ICT‐2). While the NCT area lateral of the ICT comprised significantly larger proportions and densities of y‐H2AX‐, iNOS‐, NOX2‐, MPO‐ and PAD4/MPO‐positive cells in peri‐implantitis than in periodontitis sites, a reverse difference was noted for the area proportion and density of 8‐OHdG‐positive cells in the PE. Conclusions It is suggested that peri‐implantitis lesions are associated with an enhanced and upregulated host response and contain larger numbers of neutrophils, macrophages and iNOS‐positive cells than periodontitis lesions.