The effect of the nonsteroidal anti‐inflammatory drug flurbiprofen has been studied in the ligature‐induced and spontaneous periodontitis model in the rhesus monkey, Macaca mulatta. Twenty‐four adult monkeys with incipient periodontitis were divided into three disease‐matched groups. Two groups received flurbiprofen at dosages of either 0.27 mg/kg/d or 7.1 mg/kg/d delivered systemically via osmotic minipump. A split‐mouth approach was used, placing ligatures on one side and monitoring the progression of periodontitis at regular intervals for 6 months. Clinical measurements included standardized radiographs, Ramfjord attachment level determinations and assessments of redness, edema and bleeding on probing. There was a statistically significant inhibition of attachment loss (p < 0.05), gingival redness (p < 0.05) and bleeding on probing (p < 0.05) in ligatureinduced and spontaneous periodontitis in the flurbiprofen‐treated animals at 6 months. Eight of 8 ligated control monkeys lost significant attachment (mean loss of 1.06 mm/site). Only 3 of 15 flurbiprofen‐treated ligated monkeys lost any significant attachment, with an overall mean loss of 0.34 mm/site, which was significantly less than the control loss of 1.06 mm/site at p = 4.46 times 10‐3. The odds of a control ligated monkey undergoing significant attachment loss in 6 months are elevated 29.3‐fold, as compared to the flurbiprofen‐treated, cohort monkey group. Flurbiprofen treatment also significantly inhibited spontaneous attachment loss for 6 months as compared to control monkeys, at p < 0.05. These data provide further evidence for the central role of cyclooxygenase products in the progression of periodontal disease. The ability of flurbiprofen to inhibit periodontal attachment loss, even in the presence of gross plaque accumulation, has significant implications for the potential use of flurbiprofen as an adjunctive periodontal therapeutic modality.