Locally delivered antibiotics are used to treat periodontitis and these agents are found to be effective in improving the treatment result. Microencapsulated minocycline hydrochloride (Arestin) has been tested and reported to provide significantly greater probing depth reduction in conjunction with scaling and root-planing than scaling and root-planing alone. Thus, it was suggested that the use of locally delivered antimicrobial agents should be incorporated as part of an optimal non-surgical therapeutic regimen. This paper evaluates the efficacy of the minocycline microspheres in patients with moderate to severe periodontitis in a model, which is a randomised, evaluator-blinded study with an open-label; four arm parallel design. The patients were selected based upon 'active' disease, as determined by at least two teeth having one site each with pocket depth (PD) > or = 6 mm and with prostaglandin E2 (PGE2) levels > 66.2 ng/ml in gingival crevicular fluid. The trial was of 6 months duration and used a formulation of minocycline microspheres containing 1 mg minocycline. Responses of groups receiving SRP followed by one dose per pocket of the minocycline microspheres (SRP + MPTS) were compared to SRP alone, MPTS alone or no treatment. There were substantially greater reductions in PD and gains in clinical attachment level (CAL) at each post-treatment time point in the SRP + MPTS group compared to the other treatment groups. PD reduction and gain in CAL at month 3 in the SRP + MPTS group vs. SRP alone was statistically significant. These data further support the adjunctive use of minocycline in a slow release vehicle for the treatment of periodontitis with SRP.