Tetracyclines are now recognized to have non-antimicrobial properties with therapeutic potential--for example, these agents can inhibit pathologic collagenolysis by blocking mammalian collagenases and other matrix-degrading metalloproteinases. In the current study, adult human subjects with moderate chronic periodontitis were administered specially formulated capsules of doxycycline, containing lower-than-usual amounts of this semi-synthetic tetracycline, on a daily basis for 2 weeks prior to a full-thickness flap procedure; control subjects were administered placebo capsules. The gingiva excised during this surgical procedure were extracted, the extracts partially purified and analyzed for collagenase activity using [3H-methyl] collagen as substrate and the techniques of SDS-PAGE/fluorography or liquid scintillation spectrometry. In the absence of any drug pre-treatment, or after a 2-wk regimen of placebo capsules, the gingival extracts exhibited pathologically-excessive mammalian collagenase activity. The 2-wk regimen of low-dose doxycycline capsules reduced this activity by approximately 60-80% (p less than 0.05 and less than 0.01, respectively); in vitro exposure of the gingival extract to doxycycline also inhibited its collagenase activity. Collagenase activity in the crevicular fluid of periodontal pockets of an additional group of subjects was also significantly reduced, as was the severity of inflammation at the same gingival sites. The results suggest that a regimen of low-dose doxycycline capsules may provide a safe (other studies indicate that this regimen may not induce tetracycline resistance in the subgingival plaque) and effective adjunct to instrumentation therapy in the management of pathologic collagenolysis in the periodontal patient. However, further studies are necessary to confirm this hypothesis.