Background: Clinical T2 or early T3 rectal cancers can be managed by definitive rectal resection and achieve high clinical complete response (cCR) with chemoradiation, thereby facilitating an intentional watch-and-wait (W&W) or organ-preservation strategy. We assessed the efficacy of neoadjuvant chemoradiation plus consolidation CAPEOX in MRI-defined low-risk rectal cancer to ascertain the proportion of patients who can achieve cCR and receive a W&W or organ-preservation approach. Methods: This prospective, single-arm, phase 2 trial enrolled patients with cT2/T3a/T3b low-risk rectal cancers that were pre-staged by magnetic resonance imaging (MRI), after excluding patients with local or systemic high-risk factors, such as mesorectal fascia, extramural vessel invasion, or mucinous differentiation. All patients concurrently received chemoradiation, followed by four 3-week cycles of the CAPEOX regimen. Following reassessment by the multidisciplinary team, patients with cCR or near-cCR received W&W/organ-preservation surgery. The primary endpoint was the 3-year organ-preservation rate. Findings: Of the 64 participants, 58 completed the treatment, with 6·4% and 33·9% grade 3–4 toxicities in the radiotherapy and consolidation CAPEOX phases, respectively, during a median follow-up of 32·7 (interquartile range [IQR] 4·3–60·3) months. Initial cCR, near-cCR, and non-cCR occurred in 33 (51·5%), 13 (20·3%), and 18 (28·2%) patients, respectively. Of the 31 cCR and seven near-cCR cases managed by WW 8 and 20 patients received local excision and radical resection, respectively, including six of seven patients with local regrowth salvage. One patient died of postoperative complications. Lung metastasis occurred in one patient with W&W and one patient with local excision, with no local recurrence and an estimated 3-year organ-preservation rate of 68·8%. The estimated 3-year CSS, non-regrowth disease-free survival, and stoma-free survival were 95·8%, 93·8%, and 84·3%, respectively. Interpretation: Chemoradiotherapy with consolidation CAPEOX for MRI-defined low-risk rectal cancer achieves high cCR and organ-preservation rate. Intentional W&W might be a safe strategy for this patient subgroup. Trial Registration: This study is registered at ClinicalTrials.gov with the identifier NCT02860234. Funding: Supported by The Beijing Municipal Science & Technology Commission Capital Clinical Research Special Fund (Z151100004015105); National Natural Science Foundation of China (81773214); Beijing Hospitals Authority Clinical Medicine Development of Special Funding Support, code: (ZYLX202116) Declaration of Interest: None to declare. Ethical Approval: The protocol and the later amendments were approved by the ethics committee of Peking University Cancer Hospital on August 06, 2016 and on December 17, 2018, respectively.