Introduction and Objectives: laparoscopic nephrectomy is a safe and effective procedure. It is now considered as a standard management for patients candidates for elective nephrectomy. Using either transperitoneal or retroperitoneal route remains an issue of debate. The aim of this study is to compare between both maneuvers in concern of different perioperative parameters. Patients and Methods: A prospective randomized study was carried out in the period from January 2011 to December 2013 and included 76 patients who underwent laparoscopic simple nephrectomy. The patients were enrolled randomly by (1:1) method into two groups,; 38 patients each. Group (A) was managed by transperitoneal approach (TP) and group (B) by retroperitoneal (RP) approach. Different perioperative parameters including operative time, complications, blood loss, perioperative cardiovascular and cerebral effects as well as a hospital stay were recorded and statistically analyzed. Results: There was no statistically significant difference between both groups regarding patient demographics or preoperative clinical data as heart rate, mean arterial pressure, mean PaCO2 and mean cerebral blood flow velocity CBFV. The same clinical criteria showed statistically significant differences in favor of the group (A) during CO2 inflation only and not throughout the procedure (p value = 0.001, 0.0001, 0.03, and 0.0001), respectively. The mean operative time, estimated blood loss, analgesia requirements, hospital stay, perioperative complications, time to resume oral feeding and to return the normal activities were in favor of the RP approach, but with statistically insignificant differences between both groups (p value = 0.663, 0.532, 0.591, 0. 135, 1, 0.058 and 0.812), respectively Conclusions: Choosing the approach for laparoscopic nephrectomy whether transperitoneal or retroperitoneal depends upon patient factors and surgeon’s preference, experience and comfort level with the approach. Associated ventilatory, hemodynamic and cerebral implications with retroperitoneoscopy are less hazardous than during transperitoneal laparoscopy. This might be beneficial for patients with compromised ventilatory, cardiac or cerebral functions.