Background: Periodontitis is an inflammatory condition of toothsupporting tissues that is usually treated by mechanical removal of plaque and microorganisms that adhere to teeth. This treatment, known as scaling and root planing, is not optimally effective. Adjunctive therapy with locally delivered antimicrobials has resulted in improved clinical outcomes such as probing depth reduction. This article reports on the efficacy and safety of locally administered microencapsulated minocycline.Methods: Seven hundred forty‐eight (748) patients with moderate to advanced periodontitis were enrolled in a multi‐center trial and randomized to 1 of 3 treatment arms: 1) scaling and root planing (SRP) alone; 2) SRP plus vehicle; or 3) SRP plus minocycline microspheres. The primary outcome measure was probing depth reduction at 9 months. Clinical assessments were performed at baseline and 1, 3, 6, and 9 months.Results: Minocycline microspheres plus scaling and root planing provided substantially more probing depth reduction than either SRP alone or SRP plus vehicle. The difference reached statistical significance after the first month and was maintained throughout the trial. The improved outcome was observed to be independent of patients’ smoking status, age, gender, or baseline disease level. There was no difference in the incidence of adverse effects among treatment groups.Conclusions: Scaling and root planing plus minocycline microspheres is more effective than scaling and root planing alone in reducing probing depths in periodontitis patients. J Periodontol 2001;72:1535‐1544.