Neoadjuvant chemoradiotherapy for rectal cancer can result in complete disappearance of tumor and involved nodes. In patients without residual tumor on imaging and endoscopy (clinical complete response cCR) a wait-and-see-policy (omission of surgery with follow-up) might be considered instead of surgery. The purpose of this prospective cohort study was to evaluate feasibility and safety of a wait-and-see policy with strict selection criteria and follow-up. Patients with a cCR after chemoradiotherapy were prospectively selected for the wait-and-see policy with magnetic resonance imaging (MRI) and endoscopy plus biopsies. Follow-up was performed 3 to 6 monthly and consisted of MRI, endoscopy, and computed tomography scans. A control group of patients with a pathologic complete response (pCR) after surgery was identified from a prospective cohort study. Functional outcome was measured with the Memorial Sloan-Kettering Cancer Center (MSKCC) bowel function questionnaire and Wexner incontinence score. Long-term outcome was estimated by using Kaplan-Meier curves. Twenty-one patients with cCR were included in the wait-and-see policy group. Mean follow-up was 25 ± 19 months. One patient developed a local recurrence and had surgery as salvage treatment. The other 20 patients are alive without disease. The control group consisted of 20 patients with a pCR after surgery who had a mean follow-up of 35 ± 23 months. For these patients with a pCR, cumulative probabilities of 2-year disease-free survival and overall survival were 93% and 91%, respectively. A wait-and-see policy with strict selection criteria, up-to-date imaging techniques, and follow-up is feasible and results in promising outcome at least as good as that of patients with a pCR after surgery. The proposed selection criteria and follow-up could form the basis for future randomized studies.