Cyclooxygenase (COX) plays an important role in the induction of pain and inflammation as well as the analgesic actions of NSAIDs and coxibs. This study evaluates the expression of the two isoforms COX-1 and COX-2 in a clinical model in which the surgical removal of impacted third molars is used to evaluate the analgesic activity of anti-inflammatory drugs. A 3 mm punch biopsy was performed on the oral mucosa overlying one impacted third molar immediately before extraction of two impacted lower third molars. After the second tooth was extracted, a second biopsy was performed adjacent to the surgical site either immediately after surgery, 30, 60 or 120 minutes after surgery. RNA was extracted from the biopsies and RT-PCR was performed to assess mRNA levels of COX-1, COX-2 and glyceraldehyde-3-phosphate dehydrogenase (G3PDH). The RT-PCR products in the biopsies were normalized to G3PDH and compared to baseline. COX-2 mRNA was progressively increased at 30, 60, and 120 minutes after surgery (P<0.05); COX-1 mRNA was transiently decreased at 60 minutes during the post-surgical period (P<0.05). The results demonstrate peripheral elevation of COX-2 following tissue injury, which may contribute to increased prostaglandin E 2 at the site of injury, pain onset and the analgesic activity of both non-selective NSAIDs and selective COX-2 inhibitors.Perspective-This clinical study uses a physiologically relevant model to determine the time course of expression of COX -1 and -2 in acute inflammation of the human oral mucosa. This study furthers our understanding of the contribution of the COX isoforms to acute pain.