PURPOSE: To estimate and compare the frequencies of inflammatory complications after third molar (M3) surgery in subjects receiving intravenous prophylactic antibiotics or saline placebo. MATERIALS AND METHODS: Using a placebo-controlled, double-blind, randomized clinical trial, the investigators enrolled a sample composed of subjects who required extraction of at least 1 impacted M3 and requested intravenous sedation or general anesthesia. The predictor variable was treatment group classified as active treatment (penicillin or clindamycin for penicillin-allergic subjects) or placebo (0.9% saline). Study medications were randomly assigned. Both surgeon and subject were blinded to treatment assignment. The medication was administered intravenously prior to any incision. The outcome variable was postoperative inflammatory complication classified as present or absent and included alveolar osteitis (AO) or surgical site infection (SSI). Other variables were demographic, anatomic, or operative. Descriptive and bivariate statistics were computed. Statistical significance was set at P < or = .05, single-tailed test of hypothesis. RESULTS: The sample was composed of 118 subjects (n = 59 per study group). In the active treatment group, there were no postoperative inflammatory complications. In the placebo group, 5 subjects (8.5%) were diagnosed with SSI, (P = .03). No subject met the case definition for AO. All SSIs were associated with the removal of partial bony or full bony impacted mandibular M3s. CONCLUSION: In the setting of third molar removal, these results suggest that the use of intravenous antibiotics administered prophylactically decrease the frequency of SSIs. The authors cannot comment on the efficacy of intravenous antibiotics in comparison to other antibacterial treatment regimens, eg chlorhexidine mouthrinse or intrasocket antibiotics.