Microbiologic criteria obtained with phase-contrast microscopy were used in a short-term, double-blind study to measure the effects of systemic tetracycline HCl on subgingival bacterial populations in advanced periodontal pockets refractory to local therapy (repeated scaling, root planing, and the subgingival administration of chemotherapeutic agents [H2O2, NaHCO3, NaCl, MgSO4]). Twenty-one subjects, selected for study, had at least one of the following conditions present after local therapy: spirochetes, motile rods, or crevicular leukocytes greater than or equal to 125 per phase-contrast microscopic field. Tetracycline HCl (1 gm/day for 14 days) was randomly distributed to 11 subjects and a placebo to ten subjects, so that neither the subjects nor investigators were aware of the prescription contents. Evaluations after two weeks disclosed that tetracycline HCl significantly reduced elevated levels of spirochetes, motile rods, and crevicular leukocytes to low or undetectable levels, whereas levels in the placebo subjects remained generally unchanged. The results clearly demonstrate the value of tetracycline HCl as an adjunct to periodontal therapy in reducing remaining suspected periodontopathic bacterial populations in advanced lesions after local therapy of scaling, root planing, and topically applied chemotherapy.