In a pilot study, patients with T1-T2 N0 rectal adenocarcinoma underwent irradiation of 25 Gy in 5 fractions followed by transanal endoscopic microsurgery 4 to 10 weeks later. We observed a 50% rate of complete dehiscence of the suture, with severe pain and impairment of quality of life in 2 cases associated with an enterocutaneous fistula in the sacral area that forced us to stop the study. Purpose: This study was undertaken to assess the short-term outcomes of neoadjuvant short-course radiation therapy (SCRT) followed by transanal endoscopic microsurgery (TEM) for T1-T2 N0 extraperitoneal rectal cancer. Recent studies suggest that neoadjuvant radiation therapy followed by TEM is safe and has results similar to those with abdominal rectal resection for the treatment of extraperitoneal early rectal cancer. Methods and Materials: We planned a prospective pilot study including 25 consecutive patients with extraperitoneal T1-T2 N0 M0 rectal adenocarcinoma undergoing SCRT followed by TEM 4 to 10 weeks later (SCRT-TEM). Safety, efficacy, and acceptability of this treatment modality were compared with historical groups of patients with similar rectal cancer stage and treated with long-course radiation therapy (LCRT) followed by TEM (LCRT-TEM), TEM alone, or laparoscopic rectal resection with total mesorectal excision (TME) at our institution. Results: The study was interrupted after 14 patients underwent SCRT of 25 Gy in 5 fractions followed by TEM. Median time between SCRT and TEM was 7 weeks (range: 4-10 weeks). Although no preoperative complications occurred, rectal suture dehiscence was observed in 7 patients (50%) at 4 weeks follow-up, associated with an enterocutaneous fistula in the sacral area in 2 cases. One patient required a colostomy. Quality of life at 1-month follow-up, according to European Organization for Research and Treatment of Cancer QLQ-C30 survey score, was significantly worse in SCRT-TEM patients than in LCRT-TEM patients (PZ.0277) or TEM patients (PZ.0004), whereas no differences were observed with TME patients (PZ.604). At a median follow-up of 10 months (range: 6-26 months), we observed 1 (7%) local recurrence at 6 months that was treated with abdominoperineal resection. Conclusions: SCRT followed by TEM for T1-T2 N0 rectal cancer is burdened by a high rate of painful dehiscence of the suture line and enterocutaneous fistula, compared to TEM alone and TEM following LCRT, which forced us to stop the study.