Background: The oncologic safety of transanal total mesorectal excision (TaTME) for rectal cancer has recently been questioned, with high local recurrence (LR) rates reported in Dutch and Norwegian experiences. The objective of this study was to evaluate the oncologic safety of TaTME in a large cohort of patients with primary rectal cancer, primarily in terms of LR, disease-free survival (DFS), and overall survival (OS). Patients and Methods: This was a prospective international registry cohort study, including all patients who underwent TaTME for primary rectal adenocarcinoma from February 2010 through December 2018. The main endpoints were 2-year LR rate, pattern of LR, and independent risk factors for LR. Secondary endpoints included 2-year DFS and OS rates. Kaplan-Meier survival analysis was used to calculate actuarial LR, DFS, and OS rates. Results: A total of 2,803 patients receiving primary TaTME were included, predominantly men (71%) with a median age of 65 years (interquartile ratio, 57–73 years). After a median follow-up of 24 months (interquartile ratio, 12–38 months), the 2-year LR rate was 4.8% (95% CI, 3.8%–5.8%) with a unifocal LR pattern in 99 of 103 patients (96%). Independent risk factors for LR were male sex, threatened resection margin on baseline MRI, pathologic stage III cancer, and a positive circumferential resection margin on final histopathology. The 2-year DFS and OS rates were 77% (95% CI, 75%–79%) and 92% (95% CI, 91%–93%), respectively. Conclusions: This largest TaTME cohort to date supports the oncologic safety of the TaTME technique for rectal cancer in patients treated in units that contributed to an international registry, with an acceptable 2-year LR rate and a predominantly unifocal LR pattern.