Introduction & Objective: The paradigm shift of minimal invasiveness in surgery, necessitates the use of methods and tools with minimal derangement of natural homostasis. For many years, N2O, inspite of being more neutral than, was not in use due to the reports that questioned its safety. Recently, there has been some doubts about the claims of its unsafety, and this has paved the way for its clinical trial. This study is about to provide more trustful evidences for judging between N2O and CO2.Materials & Methods: This clinical trial was done on patients who were candidates for laparoscopic cholecystectomy. Carbon dioxide or nitrous oxide was randomly used for the patients. The measured variables before and during the procedure were: Heart rate, mean arterial blood pressure, end-tidal CO2, minute ventilation, and O2 saturation and post operation pain. Pain, as perceived by patients, was measured after the procedure by visual analogue scale. Shoulder pain and ability to move in the bed and out of bed was recorded as proxy data for pain. Vomiting and use of analgesics and antiemetics were also recorded and compared.Results: The two groups of 32 patients in each arm of the trial were comparable to each other. While hemodynamic parameters were statistically identical, end-tidal CO2 was greater in patients of CO2 group. (32 versus 27 mmHg, P<0.001, 95% CI [2.00-7.27]). No differences were detected in pain perception and nausea/vomiting rate between two groups. Intra operative and postoperative use of analgesics and antiemetics were not statistically different between the two groups. No adverse events in either group were encountered.Conclusions: The use of N2O does not disturb respiratory system, contrary to the case of CO2. Its effect on the postoperative pain and vomiting and homodynamic variables had been reported to be different from that of CO2. But in our study, they were not different.