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ABSTRACT: After demonstration by Golub et al. of the ability of the tetracyclines to inhibit elevated collagenolytic activity in animal models of periodontal diseases, a clinical development program was initiated to demonstrate the potential of a subantimicrobial dose of doxycycline (SDD) to augment and maintain the improvements in clinical parameters of adult periodontitis (AP) afforded by conventional nonsurgical periodontal therapy. Clinical trials were carried out in which a number of different SDD dosing regimens and placebo were compared in patients administered a variety of adjunctive nonsurgical therapies. Measured parameters included levels of collagenase activity in gingival crevicular fluid (GCF) and gingival specimens, clinical attachment levels (cALv), probing pocket depths (PD), bleeding on probing (BOP), and subtraction radiographic measurements of alveolar bone height. When used as an adjunct to either scaling and root planing or supragingival scaling and dental prophylaxis, SDD was shown to reduce collagenase levels in both GCF and gingival biopsies, to augment and maintain cALv gains and PD reductions, to reduce BOP, and to prevent loss of alveolar bone height. These clinical responses arose in the absence of any significant effects on the subgingival microflora and without evidence of an increase in the incidence or severity of adverse reactions relative to the control groups. It is proposed that one of the mechanisms of action of SDD is as an inhibitor of pathologically elevated MMPs, including neutrophil and bone cell collagenases (MMP-8 and MMP-13), which are associated with the host response in chronic AP, and that SDD provides a novel systemic approach to the management of AP.