Background and study aims Colorectal polyps involving the appendiceal orifice (AO) are difficult to resect with conventional polypectomy techniques and therefore often require surgical intervention. These appendiceal polyps could potentially be removed with endoscopic full-thickness resection (eFTR) performed with a full-thickness resection device (FTRD). The aim of this prospective observational case study was to evaluate feasibility, technical success and safety of eFTR procedures involving the AO. Patients and methods This study was performed between November 2016 and December 2017 in a tertiary referral center by two experienced endoscopists. All patients referred for eFTR with a polyp involving the AO that could not be resected by EMR due to more than 50 % circumferential involvement of the AO or deep extension into the AO were included. The only exclusion criterion was lesion diameter > 20 mm. Results Seven patients underwent eFTR for a polyp involving the AO. All target lesions could be reached with the FTRD and retracted into the device. Technical success with an endoscopic radical en-bloc and full-thickness resection was achieved in all cases. Histopathological R0 resection was achieved in 85.7 % of patients (6/7). One patient who previously underwent an appendectomy developed a small abscess adjacent to the resection site, which was treated conservatively. Another patient developed secondary appendicitis followed by a laparoscopic appendectomy. Conclusion This small exploratory study suggests that eFTR of appendiceal polyps is feasible and can offer a minimally invasive approach for radical resection of these lesions. However, more safety and long-term follow-up data are needed to evaluate this evolving technique.