The purpose of this investigation was to compare ibuprofen versus an ibuprofen/acetaminophen combination for postoperative pain control in a patient model specific to teeth diagnosed with symptomatic irreversible pulpitis and symptomatic apical periodontitis. One hundred and two patients presenting with moderate to severe pain from a maxillary or mandibular posterior tooth diagnosed with symptomatic irreversible pulpitis and symptomatic apical periodontitis were included. Following local anesthetic administration, complete endodontic cleaning and shaping was performed. Patients were randomly assigned to receive identically appearing tablets of ibuprofen 200 mg or a combination of ibuprofen 200 mg/acetaminophen 216.7 mg with instructions to take 3 tablets every 6 hours as needed for pain. Patients were also given a prescription for an escape medication to take if the study medications did not adequately control their pain. A 4-day diary was used to record pain ratings and medication use. Moderate to severe pain was experienced by 59–61% of the patients on postoperative day 1 and 50–57% of the patients on day 2, with the pain ratings decreasing over the next 2 days. There were no statistically significant differences between the 2 groups in postoperative pain, percussion pain, or medication use. There was no difference between ibuprofen and the combination of ibuprofen/acetaminophen in the reduction of postoperative pain following endodontic debridement in patients with symptomatic irreversible pulpitis and symptomatic apical periodontitis.