BackgroundDexamethasone, an efficacious anti-inflammatory agent, is widely used after tooth extraction. However, its optimal injection site has yet to be investigated. PurposeWe compare the efficacy of dexamethasone injection at different sites on postoperative sequelae after extracting mandibular impacted third molars (MITMs). Study design, setting, and sampleA prospective randomized controlled trial was conducted. Healthy adults with fully MITMs scheduled for extraction were included. Exclusion criteria were 1) Patients with the systemic alteration that prevented the surgical procedure; 2) pregnancy, breastfeeding, premenstrual period; 3) hypersensitivity to the drug under test; and 4) those who did not return for postoperative follow-up at one, three, and seven days. Exposure variableThe subjects were randomized to three groups. An online randomization plan generator assigned each subject to a single treatment by randomly permuting blocks. Different sites for postoperative dexamethasone injections included the buccal side of the adjacent second molar and extraction sockets. Dexamethasone injection (4 mg) on the buccal side of the adjacent second molar (group 1), an injection on the buccal side of extraction sockets (group 2), an injection of physiological saline (0.8 mL) on the buccal side of the adjacent second molar (control). Outcome variablesThe outcome variables were postoperative facial swelling, limitation of the mouth opening, postoperative pain, and postoperative quality of life evaluation. The pain was assessed using a visual analog scale (VAS) at one, three and seven days, postoperatively. The quality of life was recorded throughout the Posse scale at seven days. CovariatesThe covariates are age, sex, length of operation, and type of impacted teeth and surgery. AnalysesThe statistical analysis was performed using ANOVA, repeated measures ANOVA, Chi-square, or Fisher’s exact tests with P-values < 0.05 considered statistically significant. ResultsOur study included 58 participants with a mean age of 19.48 ± 3.31 years; group 1 (n = 24), group 2 (n = 20), and control group (n = 14). On day three postoperative, the swelling and trismus were significantly less in group one than in the other two groups (P < 0.05), and group one had an overall postoperative quality of life compared to other groups (P < 0.05). Unaffected speech function was present in 73.7% of patients in group 1, while 50% of patients in group 2 had affected speech function three days after the operation (p < 0.05). The "unable to open mouth" of the “Eating subscale” and “felt tingling” had statistical significance (p < 0.05). ConclusionsDexamethasone injections on the buccal side of the adjacent second molar can be a viable option for treating facial swelling and limitation of mouth opening after total MITMs extraction.