The objective of the present study was to compare the efficacy of different doses of methylprednisolone on postoperative sequelae and quality of life (QoL) following surgical removal of mandibular third molars (SRM3). Fifty-two patients (16 men and 36 women, mean age 25.9 years, range: 18-39) with bilateral impacted mandibular third molars were randomly allocated into intraoperative muscular injection of either 20mg, 30mg, 40mg methylprednisolone or saline injection. Baseline measurements were obtained preoperatively and compared with assessment after one day, three days, seven days and one month. Pain and trismus were estimated by visual analog scale score and interincisal mouth opening, respectively. Subjective assessment of QoL included Oral Health Impact Profile (OHIP-14). Descriptive and generalized estimating equation analyses were made and expressed as mean values with a 95% confidence interval. Methylprednisolone revealed no significant differences in pain, trismus and QoL compared with placebo. Higher prevalence of postoperative pain and worsening in QoL were observed with increased age (P=0.00). Smoking and increased time of surgery decreased mouth opening in the early healing phase (P=0.00). The present study revealed no significant improvement of methylprednisolone on postoperative sequelae and QoL following SRM3 compared with placebo.