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Objectives Pain in dentistry is a common problem which dentists think about it. Controlling the pain in dentistry is crucial. Nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen are used worldwide for suppressing pain and inflammation. The aim of the present study was to compare the effect of preoperative ibuprofen and acetaminophen therapy on orthodontic pain with a different method. Materials and methods Samples were divided into two groups: Group I (they received placebo in first level, acetaminophen at second level, and ibuprofen at third level), group II (they received placebo in first level, ibuprofen at second level, and acetaminophen at third level). All drugs were administered single dose before treatment and the researcher put 1 month gap between levels. After using each drugs in each level, the amount of pain was measured by using a questionnaire based on several activities (chewing, in time of contacting teeth, and noncontacting) with visual analog scale (VAS) in multiple times. Results Placebo, ibuprofen, and acetaminophen have significant effect on suppressing pain before starting treatment, during chewing, in time of contacting teeth, and noncontacting (p = 0.000). Although the pain process in this study was ascendant, ibuprofen and acetaminophen were unable to reduce pain significantly in comparison to placebo. Conclusion Pain process was ascendant and the mentioned drugs were unable to reduce the pain by passing time. We could not reduce the pain process gradient by this drug dose. So, by increasing the dose, we wish to reduce orthodontic pain How to cite this article Moradinejad M, Jafari S, Kazemi P, Jafari F. Effect of Preoperative Ibuprofen and Acetaminophen on Orthodontic Pain. World J Dent 2016;7(4):182-185.