The purpose of this investigation was to determine the efficacy of minocycline hydrochloride in the management of subgingival microorganisms and periodontal disease. In a double-blind, split-mouth study, minocycline or placebo was administered systemically for 7 days to 26 adults with moderate-to-serve periodontitis. Four study groups were examined: (i) minocycline-scaled, (ii) minocycline-unscaled, (iii) placebo-scaled, and (iv) placebo-unscaled. The minocycline-scaled group responded most favorably, with improved gingival health for at least 49 days and with marked reductions in total bacterial counts and proportions of spirochetes for at least 70 days (termination of the study). Minocycline administration with no periodontal scaling and root planing also resulted major, long-lasting shifts in the subgingival microflora. Scaling alone was least effective in changing the microflora. The data indicated that minocycline may be a useful adjunct in the treatment of periodontal disease. Further studies are needed, however, to determine the long-term effect of minocycline therapy on the periodontal attachment level.