Natural orifice endoscopic full-thickness colon resection attempts to overcome the need for invasive surgery in selected colorectal indications. Because basic technical requirements have not been met so far, the aim of this study was to develop a novel technique for endolumenal colon-wedge resection addressing current shortcomings. Endoscopic full-thickness colon resection was attempted in a human cadaver model (n = 2), explanted porcine colon stumps (n = 10), and 3 acute pig models. A hypothesized colon lesion was created and retracted into an endoscopic clip closure system (ECCS). Initially used endoscopic graspers (n = 2) were replaced by a T-tag suture approach for retraction (n = 13). T-type anchors were deployed circumferentially to the lesion, which simultaneously marked resection margins. The clip was then applied for pre-resection tissue closure. The inverted tissue was excised by snare resection and was removed together with the sutures. Air leak-pressure of tissue closure was tested. Endoscopic full-thickness colon resection was achieved in 14 of 15 attempts. The mean diameter (±SD) of resected animal specimen, including the predetermined margins, was 26 ± 4 mm. Using the T-tag sutures for retraction, the defined lesion was neither touched by an endoscopic grasper nor compromised by puncturing the center. Leak pressure tests revealed a significantly higher air pressure resistance of the pre-resection ECCS closure (61 ± 5 mmHg) compared with the hand-sewn control (26 ± 7 mmHg). A novel endoscopic technique for full-thickness colon wall resection using tissue anchors for traction and an ECCS for pre-resection tissue closure appears to address several fundamental surgical principles. However, further studies are necessary before initial clinical application.