Natural Orifice Transluminal Endoscopic Surgery (NOTES) is a novel, potentially less invasive alternative to laparoscopic surgery. However, the problems of transluminal access and closure represent significant obstacles to its successful introduction in humans. Objective: to evaluate the feasibility and safety of a novel device designed for transluminal access and closure in a survival porcine model. Subjects: Four adult female Yorkshire pigs were used in the study. Interventions: While under general anesthesia, the animals were prepared with multiple tap water enemas followed by instillation of an antibiotic suspension and povidone-iodine lavage. At a distance of 15 to 20 cm from the anus, the prototype device (LSI Solutions, Victor, NY, USA) deployed a circumscribing purse-string suture around the planned incision site and subsequently used a blade mechanism to create a 2.5-cm linear incision. The transcolonic incision was then closed by cinching and securing the purse-string suture with a titanium knot by use of a separate hand-activated suture-locking device. Main Outcome Measurements: The animals were monitored daily for signs of peritonitis and sepsis and were survived for 14 days. The peritoneal cavity was examined for peritonitis, and the colonic incision site was examined for wound dehiscence, pericolic abscess formation, and gross adhesions. Tissue samples from both incisional and random peritoneal sites were obtained for histologic examination. Results: Transcolonic incision and closure were successful in all 4 animals. The device performed in a rapid and reproducible fashion. All animals recovered without septic complications. At necropsy, there was no evidence of peritonitis, abscesses, or wound dehiscence. Salpingocolonic and colovesicular adhesions were noted in 3 of 4 animals. Histologic examination revealed microabscesses at the incision site in all animals. Conclusions: The prototype incision and closure device represents a promising solution to the problems of transluminal access for NOTES. The presence of incision-related adhesions and microabscesses signal the need for further refinement in aseptic technique.