The reported therapeutic benefits of nonsteroidal anti-inflammatory drugs (NSAIDs) in slowing periodontal disease progression appear intimately linked to the effective inhibition of local prostaglandin synthesis. This randomized, partially double-blind, controlled trial was conducted to evaluate the pharmacodynamic effects of the NSAID, ketoprofen (KTP), on gingival crevicular fluid (GCF) prostanoids. 42 subjects, ages 35-57 years, with moderate to advanced adult periodontitis were recruited and monitored for 22 days. On day 1, subjects were randomized for 1 of 5 treatments: i) 0.5% KTP gel; ii) 1.0% KTP gel; iii) 1.0% KTP alternate gel; iv) 2.0% KTP gel; v) 25 mg KTP capsule (positive control). Subjects applied 1 ml of gel topically to their gingiva or administered one capsule p.o., b.i.d. for 14.5 days. GCF samples were collected from posterior, interproximal sites on days 1 (pre-dosing; 1, 2, 3, 6 h), 8 (pre-dosing; 2 h), 15 (pre-dosing; 2 h) and 22 (post-treatment). GCF levels of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) were determined using RIA, and expressed in ng/ml and % reduction from baseline (%Effect). Neither a significant difference among groups nor a dose response in % effect for either prostanoid was evident, both overall and among cohorts with elevated baseline mediator levels ([PGE2]>34 ng/ml; [LTB4]>300 ng/ml). When data were combined from all groups, significant (p<0.01) % reductions in GCF PGE2 were noted at 1 and 2 h post-dosing (29% and 24% respectively). In comparing topical versus systemic formulations, all topical formulations were as equipotent as systemic dosing in altering local prostaglandin levels despite lower KTP exposures with gel treatments. These data indicate that both topical and systemic KTP therapies pharmacodynamically reduce GCF PGE2 levels in adult periodontitis subjects, allowing for potential inhibition of disease progression.