Objective: To evaluate, in a simulation of surgical peri-implantitis treatment, the impact of type of handpiece, device settings, and instrumentation time on the efficacy of airflowing in cleaning the implant surface, depending on the type of bone defect and implant surface. Methods: Turned and modified surface implants (54 each) were coated with biofilm imitation and mounted on resin models replicating purely horizontal or circumferential intraosseous peri-implant defects (both 5 mm deep). Implants were instrumented with an airflowing device using a supra- or submucosal handpiece, with three settings: (a) power 5, 5 s (b) power 10, 5 s, and (c) power 5, 15 s per implant/defect sextant. Results: The amount of residual biofilm imitation was associated with defect configuration, type of handpiece, and device settings (p < 0.15); implant surface did not have an effect. In horizontal defects, with the supramucosal handpiece, only 3 of 54 implants showed > 5% residual biofilm imitation and 23 of 54 implants were completely clean; with the submucosal handpiece, 12 of 18 implants showed ≤ 5% residual biofilm imitation when used for 15 s/sextant, yet none were completely clean. In intraosseous defects, all implants presented ≤ 5% residual biofilm imitation and 10 of 18 implants were completely clean with the submucosal handpiece used for 15 s/sextant; the supramucosal handpiece was largely inefficacious. Conclusion: Within the limitations of this laboratory study, peri-implant bone defect configuration should dictate the choice of airflowing handpiece (i.e., for horizontal defects, the supramucosal handpiece; for intraosseous defects, the submucosal handpiece) and intrasurgical airflowing requires a prolonged instrumentation time, but not increased power.