Locally delivered antimicrobials represent an expanding class of therapeutics that may complement conventional mechanical treatments for chronic periodontitis. Currently available locally delivered antimicrobials include a tetracycline fiber, chlorhexidine chip, doxycycline gel, and newly approved minocycline microspheres. This last therapeutic is formulated to contain 3 mg polyglycolide-co-dl lactide (PGLA) copolymer and 1 mg of minocycline per unit (pocket) dose. As the polymer microspheres resorb, minocycline is released locally within the periodontal pocket at effective concentrations for at least 14 days. Recently, three phase 3 human clinical trials were conducted to assess the efficacy and safety of minocycline microspheres in patients with moderate-to-advanced chronic periodontitis. Data from an open-label trial involving 173 subjects indicated that minocycline microspheres plus scaling and root planing (SRP) at baseline produced significant improvements in pocket depth (PD) (> or = 1.5 mm) at 1 and 3 months. Retreatment with minocycline microspheres at 3 and 6 months maintained these improvements for 12 months. Two concurrent, blinded studies cumulatively recruited 748 periodontitis subjects who were randomized to SRP plus minocycline microspheres, SRP plus vehicle (placebo), or SRP alone at baseline. Minocycline microspheres or the vehicle were readministered per the randomization at 3 and 6 months. Patients receiving minocycline microspheres plus SRP exhibited significantly greater PD reduction at 1, 3, 6, and 9 months compared to patients receiving SRP plus vehicle or SRP alone. Overall, mean PD reduction with adjunctive minocycline-microsphere treatment increased when patients with more advanced periodontitis (mean PD > or = 6 mm or 7 mm) were considered. Similarly, significant improvements in clinical attachment level and percent bleeding on probing were observed among advanced periodontitis patients treated with SRP plus minocycline microspheres relative to controls. Patients treated with minocycline microspheres plus SRP were 50% more likely to shift to an overall mean PD < 5 mm or to a more maintainable case definition. No increased incidence of adverse events or tetracycline resistance were observed with minocycline-microsphere treatment. The data from these clinical trials indicate that minocycline microspheres plus SRP are safe in patients and more effective than SRP alone in reducting the signs of chronic periodontitis.