Since Kalloo and colleagues first reported the feasibility and safety of a peroral transgastric approach in the porcine model in 2004, various groups have reported more complex natural orifice transluminal endoscopic surgery (NOTES) procedures, such as the cholecystectomy, splenectomy and liver biopsy, in the porcine model. Natural orifice access to the abdominal cavity, such as transgastric, transvesical, transcolonic, and transvaginal, has been described. Although a novel, minimally invasive approach to the abdominal cavity is a peroral endoscopic transgastric approach, there are still some challenging issues, such as the risk of infection and leakage, and the method of gastric closure. Hybrid-NOTES is an ideal first step in humans. Human hybrid transvaginal access has been used for years by many surgeons for diagnostic and therapeutic purposes. Here, we report a transvaginal flexible endoscopic appendectomy, with a 5-mm umbilical port using ultrasonic scissors in a 74-year-old woman with acute appendicitis.