The systemic use of a single antibiotic was compared to that of a sequential antibiotic regimen in the treatment of A. actinomycetemcomitans and/or P. gingivalis-associated periodontitis. Eleven patients with recurrent/progressive periodontitis and demonstrating subgingival infection with A.a. and/or P.g. were selected. Six patients received oral administration of doxycycline (Do), 200 mg the first day and 100 mg for 4 days thereafter, and then amoxicillin/clavulanate potassium (Au), 500 mg 3 times daily for 5 days. The other 5 patients received only doxycycline for 10 days. Eight sites with > or = 5 mm probe depth per patient were selected, of which 4 received root planing at time 0. Clinical measurements (GI and PI, probing pocket depth, probing attachment level, and bleeding upon probing/suppuration) and microbial infection levels (2 sites/patient as per DNA probe) for A.a. and P.g. were recorded at 0, 4, 12, and 25 weeks. Clinical data were subjected to statistical analysis of variance and t-tests for significance. The Do + Au groups produced significant reduction in probing pocket depth (PPD) at 4, 12, and 25 weeks (1.1, 1.3, and 1.1 mm, respectively). The Do group produced significant reduction in PPD only at 4 and 12 weeks (0.8 and 0.8 mm); the Do + Au group produced significant gain of 0.8 mm in probing attachment level at 4 and 12 weeks; and the Do + Au group in conjunction with root planing produced the most sustained reduction in PPD and gain in PAL. These findings suggest that the sequential use of multiple antibiotic agents may offer greater promise as an adjunctive treatment approach for the management of recurrent and/or progressive periodontitis than a single antibiotic regimen.