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Background: With an intentional disruption of a hollow viscus and entry into the peritoneum, natural orifice transluminal endoscopic surgery (NOTES) is one of the most controversial topics in gastrointestinal surgery. Surveys demonstrate mixed opinions of surgeons regarding NOTES. Therefore, it is imperative that one examines patient response to this new approach. After all, patient perception will affect clinical implementation, public interest, and willingness to undergo a NOTES procedure. Methods: A total of 108 patients completed a questionnaire including an informational handout with illustrative diagrams and an 11-item survey. Laparoscopic cholecystectomy (LC) and NOTES cholecystectomy via transoral, transrectal, and transvaginal routes were described. Patients were asked to select their preferred surgical technique (NOTES vs. LC) assuming comparable risks of complications and cost. Patients were also asked to identify all key reasons for their respective choice. Finally, all participants were asked to select a preferred NOTES orifice.Results: Out of 108 responses, 61% of patient preferred NOTES over laparoscopy for their cholecystectomy. Female gender was the single characteristic significantly associated with a preference for NOTES, with 70% of the 66 women choosing this approach and only 48% of the 42 men (P=0.02). Age >50 (P=0.34), college or graduate level education (P=0.44), history of a prior cholecystectomy (P=0.85) and an operation in the past 10 years (P=0.19) were not found to be significantly correlated with NOTES preference. The most commonly cited reason for choosing NOTES was less post-op pain (73%), followed closely by less family inconvenience (71%) and less risk of infection (71%). The lack of external scarring ranked fourth out of the six reasons, with 44% of patients selecting this as a factor in their decision. Other less commonly cited reasons were earlier return to work/income (59%) or sports (23%). For patients choosing laparoscopy over NOTES, more available data (86%) and surgical experience (83%) were both commonly selected factors. The oral orifice was most popular, with 64% of all participants preferring this approach.Conclusion: Female gender was significantly associated with a preference for NOTES. Other demographic factors did not correlate significantly with selection of either technique. Decreased pain, family inconvenience and risk of infection were found to be more important than scarring, earlier return to work/income or sports. The oral orifice was preferred by a majority of patients. Patients consider NOTES a reasonable alternative to laparoscopy.