Background: Post-operative pain after open cholecystectomy can result in increased oxygen consumption, increased risk of myocardial ischemia, atelectasis, pneumonia, decreased vital capacity, and increased morbidity and mortality. In this study we compared the analgesic effects of intrapleural bupivacaine with intravenous morphine post-operatively. Materials and Methods: Sixty patients who were candidates for elective open cholecystectomy were randomly divided into two groups based on randomized numbers for a double-blinded randomized clinical trial. Anesthesia technique was precisely the same for all patients. At the end of surgery, 20 cc of 0.5% bupivacaine and epinephrine with a concentration of 1/200,000 was injected intrapleurally for group B patients; whereas, 0.1 mg/kg intravenous morphine and 20cc normal saline was injected intrapleurally for group M cases. Results: In order to obtain a visual analog scale(VAS) <3, morphine consumption up to 12 hours post-op was 10.5±3.2 mg in group M which was much more than that of group B, in which this amount was 4.3±1.5 mg. This difference was statistically significant (p <0.05). The mean frequency of morphine injection was 3.7±1.3 times in group M and 1.2±0.7 times in group B and the difference in this regard was statistically significant. The patients’ first demand for morphine was 1.8±0.6 and 4.2±0.3 hours postoperatively for groups M and B respectively. The difference in this regard was statistically significant (p <0.05). Conclusion: In this study we realized that a single shot of intrapleural bupivacaine can provide an almost favorable analgesia for the management of post-operative pain due to open cholecystectomy compared to other current analgesic methods. It may reduce the related complications as well. We observed no complication due to the single shot of intrapleural bupivacaine. (Tanaffos 2010; 9(2): 50-53)