Background: One of the aims of endodontic treatment is to control preoperative and postoperative pain. The present study evaluated the effects of local and systemic ibuprofen on postoperative pain. It aimed to determine the most effective method for relieving postoperative pain due to chemomechanical preparation. Material/Methods: Ninety patients with symptomatic apical periodontitis were randomly assigned to local ibuprofen, systemic ibuprofen, and control groups (n=30 each). Chemomechanical preparations were performed using a ProTaper Universal Ni-Ti rotary file under 2.5% sodium hypochlorite and 17% ethylenediaminetetraacetic acid irrigation. After the root canals were dried with sterile paper points, while Odontocide paste was applied into the root canals of the patients in the local ibuprofen group, calcium hydroxide paste was applied into the root canals of the patients in the systemic ibuprofen and control groups. Following completion of the endodontic treat-ment procedure, 200 mg ibuprofen was prescribed to patients in the systemic ibuprofen group. Friedman and Wilcoxon tests were used for statistical analysis. Results: Posttreatment pain scores were recorded at 6, 12, 24, and 48 h using a visual analogue scale. Although there were no significant differences between the local ibuprofen group (Odontocide) and the control group (Ultracal) (P > 0.05), pain scores in the systemic group (Ultracal+200 mg ibuprofen) were significantly lower than those in the other 2 groups (P < 0.05). Conclusions: These results indicate that systemic administration of ibuprofen is effective for postoperative pain relief.