This investigation was designed to evaluate the efficacy of an erbium, chromium-doped yttrium, scandium, gallium and garnet (Er,Cr:YSGG) laser (laser group) compared to conventional mechanical debridement (control group) in the treatment of peri-implantitis. In a double-blinded, randomized, controlled clinical trial, 32 patients with 88 implants with peri-implantitis were randomly assigned to either group. Statistical analyses were performed at 9 months for both groups. The laser-treated group showed a statistically significant reduction in probing depth (PD) compared to the control group (P = .04), but no statistically significant differences were observed for clinical attachment level gain (P = .29) or reduction of bleeding on probing (P = .09). In the subgroup analysis, mandibular single implants with screw-retained restorations treated with Er,Cr:YSGG demonstrated a statistically significant decrease in PD (P < .05) compared to all other groups. A complete resolution of peri-implantitis was achieved in 21% of implants in the test group and 5% of implants in the control group. Er,Cr:YSGG laser is an efficacious therapeutic tool to treat peri-implantitis, achieving greater PD reduction than conventional mechanical debridement alone. Er,Cr:YSGG laser also showed increased benefits in the treatment of mandibular, screw-retained, and single-unit implants compared to the sole use of conventional mechanical debridement.