OBJECTIVE To evaluate the transperitoneal and retroperitoneal approaches for endoscopic radical nephrectomy in a prospective randomized manner to assess the possible differences in the outcome related to patients' morbidity and technical difficulty for the surgeon. METHODS A total of 40 patients with Stage cT1-T2 were randomized into two equal groups: laparoscopic radical nephrectomy (LRN) and retroperitoneoscopic radical nephrectomy (RRN). The patient demographics and tumor characteristics were comparable. Two surgeons with differing experience performed an equal number of procedures in both treatment arms. The outcome was compared, and the technical difficulty for the surgeon and assistant was assessed with the European scoring system. RESULTS All procedures were completed without a need for conversion. No statistically significant differences were found between the two approaches in terms of the number and size of the trocars used, length of incision, specimen weight, pathologic stage, operative time, need for additional procedures such as adrenalectomy and/or lymph node sampling, estimated blood loss, need for blood transfusions, analgesic requirement, length of hospital stay, or the incidence of minor or major complications. All patients in the LRN group resumed oral intake on postoperative day 1, but only 75% did so in the RRN group. The technical difficulty score for either the surgeon or the assistant did not differ significantly between the two groups. Both approaches allowed complete tumor excision. The robotic assistance system (AESOP) was more difficult with RRN compared with LRN. CONCLUSIONS This first prospective randomized study comparing LRN and RRN did not find any real difference between the two approaches in relation to patient morbidity or the technical difficulty for the surgeon.