Background and Aims: The X-Tack endoscopic HeliX tacking system (Apollo Endosurgery, Austin, Tex, USA) has recently been approved by the Food and Drug Administration and is slowly gaining popularity for the closure of large tissue defects. Despite its increasing use, outcome data of using the X-Tack system for mucosal defect closure after endoscopic resection (ER) are limited. Here, we report the follow-up outcomes of a series of cases that underwent ER and mucosal closure aided by the HeliX tacking system. Methods: We identified a total of 5 cases in which the X-Tack system and endoclips were used for mucosal defect closure after ER. The cases involved ER of large and/or flat polyps in the duodenum and colon. The patients were followed up at 4, 6, and 9 months after ER. Results: In all cases, X-Tacks with endoclips achieved complete closure of the large mucosal defects. None of the patients experienced any adverse events, such as abdominal pain or bleeding. At follow-up, the X-Tacks either fell off or were seen grouped or situated as a single piece (tack) in the mucosa where initially placed. None of the endoclips were found during the follow-up endoscopic examinations. Conclusions: The X-Tack system together with endoclips facilitated complete closure of large mucosal defects, especially for lesions located in difficult locations. At follow-up, several retained X-Tacks were found either in groups or as a single piece. The X-Tacks seen in groups will likely fall off with repetitive pulling forces with food or feces. However, the single tacks that were secured in the wall may stay indefinitely. The novel HeliX tacking system seems to be a promising aid for the effective closure of large mucosal defects; however, further studies are needed to assess the long-term outcome of this novel system.