Transanal endoscopic microsurgery (TEM) allows minimally invasive full-thickness local excision of rectal tumors with perirectal fat dissection. Thirty-seven patients with extraperitoneal rectal carcinoma underwent full thickness TEM resection for T1 (10 patients), T2 (20 patients), and T3 (6 patients) lesions, with associated radiotherapy in the second and third group. One patient, staged as T2, underwent full-dose radiotherapy and TEM and the pathologist did not find cancer cells on the specimen (pT0). Morbidity included would dehiscence and stool incontinence in three and two patients, respectively, that resolved with medical therapy and rectovaginal fistula in one patient that required reoperation. No perioperative mortality was observed. Mean follow-up was 35 months (range 17-60 months), with two local recurrences (5.4%) that were successfully retreated. Cancer-related mortality due to systemic metastases was 8.1%. This is the first clinical study reporting on the application of TEM combined with radiotherapy for the treatment of T2 and T3 rectal cancer in selected patients. This approach is feasible, safe, and appears to be effective at the present duration of follow-up, with preservation of normal and sphincter function.