Background: Although the concept of natural orifice transluminal endoscopic surgery (NOTES) as a minimally invasive surgical technique is gaining increasing popularity, patient perception toward NOTES is unclear. Because cholecystectomy is the most common laparoscopic procedure, the concept of NOTES was examined in this context. Aim: To evaluate patient perception of NOTES as a potential technique for a cholecystectomy. Patients: Those patients with an intact gallbladder who were undergoing an EUS or an ERCP for evaluation of abdominal pain, pancreatitis, or suspected choledocholithiasis. Setting: Tertiary-referral center. Design: Cross-sectional survey. Methods: One hundred patients were given a questionnaire that described the technique, the complication rates, and benefits of laparoscopic cholecystectomy (LC). The concept of NOTES was then described in detail, with possible orifices being the mouth, the rectum, and the vagina. Patients were queried about their preference for a cholecystectomy technique (LC vs NOTES), choice of orifice, and the risks that they were willing to undergo for NOTES. Results: Of the 100 patients, 78% preferred NOTES, and 22% preferred LC. The mean age of the patients was 45 years; 36% of patients were men, 70% were white, and 83% had undergone a prior endoscopy; no significant differences were observed between the NOTES and LC groups for these characteristics. In multivariable modeling, those with age ≤ 50 years (odds ratio [OR] 1.3, P = .61), female sex (OR 2.1, P = .14), and prior endoscopy experience (OR 2.2, P = .19) were more likely to prefer NOTES than an LC. There was no difference in preference for NOTES between whites and nonwhites (OR 1.0, P = .98). The most common reasons for NOTES preference were lack of external pain (99%) and scarring (89%). Among the patients who preferred NOTES, for both men (23/25 [92%]) and women (43/53 [81%]), the oral route was the preferred orifice. A decreasing trend of patient preference for NOTES was observed with increased procedural complications: patient preference was 100% if complications were <3%, 97% if complications were equal to 3%, 15% if complications were 6%, and 6% if complications were 9%. Limitations: A selective cohort of patients was evaluated. Conclusions: Patients preferred NOTES to laparoscopy as the technique for cholecystectomy as long as the complication rates were comparable with current standards of LC. The oral orifice appeared to be the preferred approach for most patients. Given this favorable perception, further innovations in NOTES-related technology and refinements in procedural technique are justified. © 2008 American Society for Gastrointestinal Endoscopy.