Objectives: Natural orifice translumenal endoscopic surgery (NOTES) is evolving as a promising alternative for abdominal surgery. IMTN Registry was designed to prospectively document early results of natural orifice surgery among a large group of clinical cases. Methods: Sixteen centers from 9 countries were approved to participate in the study, based on study protocol requirements and local institutional review board approval. Transgastric and transvaginal endoscopic natural orifice surgery was clinically applied in 362 patients. Intraoperative and postoperative parameters were prospectively documented. Results: Mean operative time for transvaginal cholecystectomy was 96 minutes, compared with 111 minute for transgastric cholecystectomy. A general complication rate of 8.84% was recorded (grade I-II representing 5.8%, grade III-IV representing 3.04%). No requirement for any analgesia was found in one fourth of cholecystectomy and appendectomy patients. Conclusions: Results of clinical applications of NOTES in the IMTN Study showed the feasibility of different methods of this new minimally invasive alternative for laparoscopic and open surgery.