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Radical surgery is associated with significant perioperative mortality in elderly and comorbid populations. Emerging data suggest for patients with a clinical complete response after neoadjuvant chemoradiotherapy that a watch-and-wait approach may provide equivalent survival and oncological outcomes.The purpose of this study was to compare the cost-effectiveness of watch and wait and radical surgery for patients with rectal cancer after a clinical complete response following chemoradiotherapy.Decision analytical modeling and a Markov simulation were used to model long-term costs, quality-adjusted life-years, and cost-effectiveness after watch and wait and radical surgery. Sensitivity analysis was used to investigate the effect of uncertainty in model parameters.A third-party payer perspective was adopted.Patients included in the study were a 60-year–old male cohort with no comorbidities, 80-year–old male cohorts with no comorbidities, and 80-year–old male cohorts with significant comorbidities.Radical surgery and watch-and-wait approaches were studied.Incremental cost, effectiveness, and cost-effectiveness ratio over the entire lifetime of the hypothetical patient cohorts were measured.Watch and wait was more effective (60-year–old male cohort with no comorbidities = 0.63 quality-adjusted life-years (95% CI, 2.48–3.65 quality-adjusted life-years); 80-year–old male cohort with no comorbidities = 0.56 quality-adjusted life-years (95% CI, 0.52–1.59 quality-adjusted life-years); 80-year–old male cohort with significant comorbidities = 0.72 quality-adjusted life-years (95% CI, 0.34–1.76 quality-adjusted life-years)) and less costly (60-year–old male cohort with no comorbidities = $11,332.35 (95% CI, $668.50–$23,970.20); 80-year–old male cohort with no comorbidities = $8783.93 (95% CI, $2504.26–$21,900.66); 80-year–old male cohort with significant comorbidities = $10,206.01 (95% CI, $2762.014–$24,135.31)) independent of patient cohort age and comorbidity. Consequently, watch and wait was more cost-effective with a high degree of certainty (range, 69.6%–89.2%) at a threshold of $50,000/quality-adjusted life-year.Long-term outcomes were derived from modeled cohorts. Analysis was performed for a United Kingdom third-party payer perspective, limiting generalizability to other healthcare contexts.Watch and wait is likely to be cost-effective compared with radical surgery. These findings strongly support the discussion of organ-preserving strategies with suitable patients.