The primary goal of this study was to characterize the release profile of doxycycline hyclate (8.5% w/w) from a biodegradable controlled-release delivery system (DH) placed in periodontal pockets. Pharmacokinetic data were obtained from gingival crevicular fluid (GCF), saliva, and serum of adult periodontitis patients. These results were compared to those obtained from individuals who received standard oral doses of doxycycline hyclate (200 mg on day 0, then 100 mg/day for 7 days). All participants presented with multiple pockets ≥ 5 mm that bled upon probing. At the baseline visit patients receiving local drug delivery had all pockets ≥ 5 mm that bled upon probing on one side of the mouth filled with DH. Drug retention was enhanced with 1 of 2 periodontal dressings (non-eugenol [NE] or 2-octyl cyanoacrylate [2-octyl]). Doxycycline concentrations were analyzed with the aid of reverse phase high performance liquid chromatography. GCF, saliva, and serum samples were obtained just prior to drug delivery and then at hours 2, 4, 6, 8, 18, 24 and days 2, 3, 5, 7, and 8. GCF and saliva samples were also obtained at days 10, 14, 21, and 28. Thirty two subjects participated in the study; 13 in the NE group, 13 in the 2-octyl group, and 6 in the group taking oral doxycycline. The release of doxycycline in the GCF peaked at 2 hours (1473 μg/ml in the NE group, and 1986 μg/ml in the 2-octyl group). The mean concentration at day 7 was 309 μg/ml for the NE group and 148 μg/ml for the 2-octyl group. Minimal levels of drug were detected in the GCF of the oral doxycycline group with a peak concentration of 2.53 μg/ml at 12 hours. Salivary concentrations for both local delivery groups peaked at hour 2 (4.05 μg/ml for the NE group and 8.78 μg/ml for the 2-octyl group); by the end of day 1 levels were ≤ 2 μg/ml. For subjects who took the oral doxycycline, salivary concentrations never exceeded 0.11 μg/ml. Serum concentrations of doxycycline for individuals receiving the local drug delivery never exceeded 0.1 μg/ml. For the oral doxycycline group serum concentrations ranged from 0.91 to 2.26 μg/ml over the 8 days data were collected. The high concentration of drug available at the treated sites coupled with the relatively low levels in the saliva and almost non-existent levels in the serum indicate that this biodegradable controlled-release delivery system displays an appropriate pharmacokinetic profile for the delivery of doxycycline into periodontal pockets. J Periodontol 1998;69:1085-1091.