Background: Chemotherapeutic agents (ChAs) are considered an integral part of current treatment protocols for the decontamination of titanium implants with peri-implantitis, based on their antimicrobial effect. Despite the proven antimicrobial effect of ChAs on titanium-bound biofilms, previous studies have elucidated an unexpected disassociation between bacterial reduction and biologically acceptable treatment outcomes. In this study, the authors hypothesize that ChAs residues alter titanium physicochemistry and thus compromise cellular response to decontaminated surfaces. Methods: Grit-blasted acid-etched titanium disks were contaminated with multispecies microcosm biofilms grown from in vivo peri-implant plaque samples. To simulate implant decontamination, the contaminated disks were burnished with 0.12% chlorhexidine, 20% citric acid, 24% EDTA/1.5% NaOCl, or sterile saline and assessed surface physicochemical properties. Sterile untreated surfaces were the controls. The biologic effects of decontamination were assessed via cell proliferation and differentiation assays. Results: Bacterial counts after decontamination confirmed that the ChAs were antimicrobial. X-ray photoelectron spectroscopy invariably detected elemental contaminants associated with each ChA molecule or salt that significantly altered wettability compared with controls. Notably, all surfaces with ChA residues showed some cytotoxic effect compared with controls (P <0.05). Increased cell counts were consistently found in the saline-Treated group compared with chlorhexidine (P = 0.03). Interestingly, no association was found between antimicrobial effect and cell counts (P >0.05). Conclusions: ChA-specific residues left on the titanium surfaces altered titanium physical properties and adversely affected the osteoblastic response irrespective of their observed antimicrobial effect. Chlorhexidine may compromise the biocompatibility of titanium surfaces, and its use is not recommended to detoxify implants. Sterile saline, citric acid, and NaOCl-EDTA may be proposed for use in the treatment of periimplantitis. Contrary to previous studies that recommended the selection of ChAs for the decontamination of titanium implants according to their antimicrobial effects, the present study demonstrated that the restoration of the biocompatibility of contaminated titanium surfaces is also contingent on the preservation of titanium material properties.