Simple SummaryEndorectal ultrasound and rectal magnetic resonance are sometimes unable to differentiate between stages T2 and T3 in rectal adenomas that are possible adenocarcinomas, and between stages T1 and T2 in rectal adenocarcinomas. These cases of diagnostic uncertainty raise a therapeutic dilemma: should they be treated with transanal endoscopic surgery (TES) or total mesorectal excision (TME)? We present an observational study of a cohort of 803 patients who underwent TES between 2004 and 2021. Five hundred and twenty-nine patients operated on for adenoma (group I) and 109 for low-grade adenocarcinoma (group II) were included. Diagnosis was uncertain in 113/529 patients (21.4%) in group I, and in 8/109 (7.3%) in group II. The definitive pathology diagnosis showed 17 cases in group I (15%) to be adenocarcinomas greater than T1, and two cases in group II. On the strength of these data, in cases of diagnostic uncertainty we recommend TES as the initial indication.Background: Endorectal ultrasound and rectal magnetic resonance are sometimes unable to differentiate between stages T2 and T3 in rectal adenomas that are possible adenocarcinomas, or between stages T1 and T2 in rectal adenocarcinomas. These cases of diagnostic uncertainty raise a therapeutic dilemma: transanal endoscopic surgery (TES) or total mesorectal excision (TME)? Methods: An observational study of a cohort of 803 patients who underwent TES from 2004 to 2021. Patients operated on for adenoma (group I) and low-grade T1 adenocarcinoma (group II) were included. The variables related to uncertain diagnosis, and to the definitive pathological diagnosis of adenocarcinoma stage higher than T1, were analyzed. Results: A total of 638 patients were included. Group I comprised 529 patients, 113 (21.4%) with uncertain diagnosis. Seventeen (15%) eventually had a pathological diagnosis of adenocarcinoma higher than T1. However, the variable diagnostic uncertainty was a risk factor for adenocarcinoma above T1 (OR 2.3, 95% CI 1.1–4.7). Group II included 109 patients, eight with uncertain diagnosis (7.3%). Two patients presented a definitive pathological diagnosis of adenocarcinoma above T1. Conclusions: On the strength of these data, we recommend TES as the initial indication in cases of diagnostic uncertainty. Multicenter studies with larger samples for both groups should now be performed to further assess this strategy of initiating treatment with TES.