Background Endoscopic full-thickness resection (EFTR) has been shown to be a feasible and safe technique in several studies since the introduction of the full-thickness resection device (FTRD(R)). This study aimed to describe our clinical experience and long-term follow up in in patients who underwent EFTR of benign and malignant colon lesions using FTRD. Methods All patients with difficult adenomas or early adenocarcinomas referred for an EFTR to two centres in Denmark were included in this prospective consecutive study. The primary outcome was technical success with R0 resection and relapse-free follow up. The secondary outcome was procedure-related adverse events. Results Twenty-six patients were enrolled in the study. Technical success was achieved in 81% patients and R0 resection rate was 86%. Full-thickness resection was achieved in 86% patients. In 13 patients with malignant lesions, we obtained follow-up in 10 cases (two patients underwent surgery and one was non-compliant). Findings of the three-month follow up showed no residual tumour in all 10 cases. At the 12-month follow up, one patient had a late relapse. There were no residual or recurrent adenomas in the benign subgroup. Overall, adverse events were observed in 11.5% (3/26) patients with a perforation rate of 7.7%. Conclusion EFTR with FTRD proves to be an additional technique for the treatment of difficult non-lifting colorectal lesions. For malignant lesions, EFTR is technically safe and feasible and can potentially treat small early low-risk tumours; however, some cases may require subsequent surgery according to the histological staging observed in the resected specimen.