The purpose of this study was to determine the clinical, microbial, and radiographic effects of local minocycline combined with surgical treatment of peri-implantitis. Fifty patients with peri-implantitis were recruited, and surgical treatment with the local application of either minocycline or placebo ointment was performed. The application of minocycline was repeated with supragingival debridement at 1, 3, and 6 mo postoperatively. Plaque index, gingival index (GI), probing pocket depth (PPD), and bleeding/suppuration on probing were measured at baseline and 1-, 3-, and 6-mo evaluations. The change in supporting bone level (SBL) measured with cone beam computed tomography was analyzed between baseline and 6 mo. Microbial analysis was performed with real-time polymerase chain reaction. Both groups exhibited improvements in clinical and radiographic measurements after surgical treatment. There was a significant difference in the changes of mean PPD between the test and control groups (2.68 ± 1.73 and 1.55 ± 1.86 mm, respectively, P = 0.039). The changes of mean GI and SBL differed significantly between the groups (ΔGI: 0.83 ± 0.60 and 0.40 ± 0.68; ΔSBL: 0.72 ± 0.56 and 0.31 ± 0.49 mm, respectively, P = 0.026 and 0.014). Treatment success rates (defined as PPD <5 mm, absence of bleeding/suppuration on probing, and no further bone loss) were 66.7% and 36.3% in the test and control groups, respectively. The count of red complex bacteria tended to decrease in both groups until 6 mo; however, no significant intergroup difference was found. None of the patients in the test group carried Porphyromonas gingivalis or Tannerella forsythia at 6 mo. These findings indicate that the repeated local delivery of minocycline combined with surgical treatment provides significant benefits in terms of clinical parameters and radiographic bone fill, with a higher treatment success rate in the short healing period (cris.nih.go.kr KCT0002844).