Objective The goal of this preliminary randomized prospective clinical trial was to compare the analgesic efficacy and the reduction in trismus of preoperative rofecoxib, intraoperative dexamethasone, and both rofecoxib and dexamethasone following third molar extraction surgery. Study design Thirty-five subjects requiring surgical removal of at least 1 partial bony impacted mandibular third molar were invited to participate in this double-blind and double-dummy placebo-controlled clinical trial. Subjects were randomly assigned into 1 of 4 treatment groups: (1) placebo po preoperatively and placebo IV intraoperatively; (2) rofecoxib 50 mg po preoperatively and placebo IV intraoperatively; (3) placebo po preoperatively and dexamethasone10 mg IV intraoperatively; and (4) rofecoxib 50 mg po preoperatively and dexamethasone 10 mg IV intraoperatively. Subjects completed a diary assessing postoperative pain onset and intensity using categorical and visual analogue scales. Interincisal opening was assessed 1, 2, 3, and 7 days postoperatively using a Therabite ruler. Results This randomized controlled clinical trial enrolled 35 subjects. Two subjects did not meet the inclusion criteria and 4 did not return completed diaries. The mean age of the remaining 29 subjects (11 males, 18 females) was 22.8 years (+/- 0.6 year). The active treatments tended to delay the need for initial pain medication. When compared to other active treatments and to placebo, the combination of preoperative rofecoxib and intraoperative dexamethasone significantly reduced initial pain intensity ( P < .05). Baseline interincisal opening was 52.6 mm (+/- 6.2). The greatest decrease in interincisal opening was 43.3% for the placebo group at 24 hours. Preoperative rofecoxib alone showed a decrease in interincisal opening of 42.3% ( P = ns) at 24 hours. Intraoperative dexamethasone alone showed a decrease in the interincisal opening of 24.1% of baseline ( P < .05 vs placebo). The group receiving the combination of rofecoxib and dexamethasone showed a decrease in interincisal opening of 23.7% of baseline ( P < .05 vs placebo). Conclusions The results of this trial indicate that the use of intraoperative dexamethasone is an effective therapeutic strategy for limiting trismus following surgical removal of impacted third molars. The combination of preoperative rofecoxib 50 mg and intraoperative dexamethasone 10 mg was most effective in minimizing pain and trismus following third molar surgery.