In vitro tests in our laboratory have shown that 40% tetracycline HCl in a white petrolatum carrier (TTC-WP) has potential as a sustained release, autodissipating system. The present study tested subgingival placement of TTC-WP via syringe in vivo. Quadrants (2 diseased sites in each) in 9 patients with moderate/severe periodontitis were randomly assigned to receive the following treatments: (1) TTC-WP; (2) WP only; (3) scaling and root planing; (4) untreated control. TTC release into gingival crevicular fluid (GCF) over time (baseline, 1, 8, 24, 72 and 168 h) was measured using an agar diffusion bioassay. Clinical parameters and subgingival bacterial morphotypes (darkfield analysis) were also evaluated over time (baseline, 2, 4, 8, 12 weeks). Results indicated that TTC-WP was easily placed into periodontal pockets and biologically effective TTC was released into GCF for at least 3 days (mean concentration = 115.8 +/- 43.1 micrograms/ml at 3 days). TTC-WP reduced probing pocket depths and bleeding on probing relative to baseline measurements for 8-12 weeks post-treatment, and reduced %s of motile rods and spirochetes, with an accompanying increase in cocci, for 2-8 weeks. Similar effects were noted in the scaled and root-planed sites, but for a longer duration. TTC-WP and WP were clinically dissipated after 2 weeks and no adverse tissue reactions were observed. From these findings, subgingival TTC-WP cannot replace scaling and root planing therapy, but has characteristics useful in subgingival plaque control.