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Background: Postoperative pain is a usual phenomenon that can cause some problems such as increased blood pressure, increased oxygen use, an increased risk of myocardial infarction (MI). Like any other medical procedure, orthopedic surgery is associated with pain and complications. Recently, doxepin has been used as a tricyclic anti depressant (TCA) to decrease pain. Therefore, we designed this study to evaluate the effects of doxepin on the postoperative pain following lower limb orthopedic surgery. Methods: This randomized double blind placebo controlled trial was performed on 102 lower limb orthopedic patients in three groups of 34. The first two group received 50 and 100 mg doxepin while the last group received placebo. Patients aged between 18 and 65 years. Data was collected by a standard questionnaire and analyzed by analysis of variance (ANOVA) and chi-square test in SPSS. Findings: No significant differences were observed between the three groups in terms of pain intensity before or after surgery (P = 0.58). The only significant difference was seen between the first (50 mg doxepin) and placebo groups during the first 24 hours after surgery (P = 0.25). The groups were not different in demographic characteristics (age, gender, or education), either. In addition, received doses of morphine, and the frequency of nausea, vomiting, itchiness, and other side effects were not significantly different between groups. Conclusion: According to our results, doxepin was not effective on pain reduction after lower limb orthopedic surgery. We therefore hypothesize doxepin to have more effects on chronic pains than acute pains. [ABSTRACT FROM AUTHOR]