The feasibility and safety of Natural Orifice Translumenal Endoscopic Surgery (NOTES) transanal endoscopic rectosigmoid resection using transanal endoscopic microsurgery (TEM) was previously demonstrated in human cadavers and a porcine survival model. We report the first clinical case of a NOTES transanal resection for rectal cancer using TEM and laparoscopic assistance, performed by a team of surgeons from Barcelona and Boston with extensive experience with NOTES and minimally invasive approaches to colorectal diseases.