Background: Resected rectal polyps with deep invasion into the submucosa (pT1b-sm2,3) or the muscle layer (pT2) are currently confronted with surgery due to non-curative resection. Aims: We evaluated the efficacy, safety, and locoregional control of adjuvant radiotherapy (RT) and/or chemotherapy (CT) following endoscopic KAR (knife-assisted resection) in patients with invasive early rectal cancers who are unwilling or unsuitable for additional surgical resection. Methods: Fifty-one patients with early rectal cancers, pT1b or pT2, underwent post-resection adjuvant RT and/or CT in 15 centers worldwide. “En bloc” macroscopic resection, R0 resection, recurrence rate, and adverse events following resection and adjuvant therapy were recorded in a multicenter retrospective cohort study. Results: Diagnostic staging (38/51, 75%) was the main reason for ELE. Macroscopic “en bloc” resection was demonstrated in 50/51 (98%), with an average follow-up of 20.6 months. Endoscopic recurrence occurred in 7/51 (13.7%) of patients, with mean time for diagnosis of recurrence at 8.9 months. Adjuvant therapy consisted of RT in 49.0% (25/51), CT in 11.8% (6/51), and combined CRT in 39.2% (20/51) of the cases. Perforation, severe post-procedural bleeding, and incontinence were the most frequent complications. The absence of superficial ulceration was associated with macroscopic complete resection, while the lesions with lower budding stage, clear lateral margins, lesion size <40 mm, and needle-type knife used were associated with less endoscopic recurrencies. Conclusions: Our data investigated adjuvant RT and/or CT after endoscopic KAR of infiltrative rectal cancers (pT1bsm2,3-pT2) as being safe and effective for locoregional control and providing a non-surgical treatment option for patients with a non-curative resection.