Introduction Pain management is very important in endodontic practice. The aim of this study was to compare the effect on pain relief of on-demand versus regular prescription of ibuprofen after single-visit root canal treatment in teeth with irreversible pulpitis. Methods Sixty mandibular and maxillary molar teeth with irreversible pulpitis without spontaneous pain had single-visit root canal treatment. After this treatment, patients were randomly allocated to 2 groups of 30 patients each. Patients in group 1 received a single dose of 400 mg ibuprofen and a rescue bag of the same medication to use if they felt pain and needed further medication. Patients in group 2 received the same medication as group 1 patients after treatment, and they were also provided with a prescription to use 400 mg ibuprofen every 6 hours for at least 24 hours. The patients were asked to rate their pain on a visual analog scale for up to 48 hours after treatment. The data were analyzed with Mann-Whiney, chi-square, Fisher exact, and McNemar tests. Results Two patients were excluded because they did not return their pain record forms. Data analysis of the remaining 58 patients showed no significant difference in pain felt by the patients in groups 1 and 2 at either 24 or 48 hours after treatment (P =.849 and P =.732, respectively). Patients in group 2 used significantly more medication compared with patients in group 1 (P =.04). Conclusions In patients who had irreversible pulpitis with no moderate to severe spontaneous pain, prescribing ibuprofen on a regular basis after root canal treatment had no significant effect on pain relief compared with an on-demand regimen up to 48 hours after treatment. Copyright © 2014 American Association of Endodontists.