IMPORTANCE Although American guidelines recommend use of adjuvant chemotherapy in patients with locally advanced rectal cancer, individuals who achieve a pathological complete response (PCR) following neoadjuvant chemoradiotherapy are less likely to receive adjuvant treatment than incomplete responders. The association and resection of adjuvant chemotherapy with survival in patients with PCR is unclear. OBJECTIVE To determine whether patients with locally advanced rectal cancer who achieve PCR after neoadjuvant chemoradiation therapy and resection benefit from the administration of adjuvant chemotherapy. DESIGN, SETTING, AND PARTICIPANTS This retrospective propensity score-matched cohort study identified patients with locally advanced rectal cancer from the National Cancer Database from 2006 through 2012.We selected patients with nonmetastatic invasive rectal cancer who achieved PCR after neoadjuvant chemoradiation therapy and resection. EXPOSURES We matched patients who received adjuvant chemotherapy to patients who did not receive adjuvant treatment in a 1:1 ratio.We separately matched subgroups of patients with node-positive disease before treatment and node-negative disease before treatment to investigate for effect modification by pretreatment nodal status. MAIN OUTCOME AND MEASURES We compared overall survival between groups using Kaplan-Meier survival methods and Cox proportional hazards models. RESULTS We identified 2455 patients (mean age, 59.5 years; 59.8%men) with rectal cancer with PCR after neoadjuvant chemoradiation therapy and resection.We matched 667 patients with PCR who received adjuvant chemotherapy and at least 8 weeks of follow-up after surgery to patients with PCR who did not receive adjuvant treatment. Over a median follow-up of 3.1 years (interquartile range, 1.94-4.40 years), patients treated with adjuvant chemotherapy demonstrated better overall survival than those who did not receive adjuvant treatment (hazard ratio, 0.44; 95%CI, 0.28-0.70). When stratified by pretreatment nodal status, only those patients with pretreatment node-positive disease exhibited improved overall survival with administration of adjuvant chemotherapy (hazard ratio, 0.24; 95%CI, 0.10-0.58). CONCLUSIONS AND RELEVANCE The administration of adjuvant chemotherapy in patients with rectal cancer with PCR is associated with improved overall survival, particularly in patients with pretreatment node-positive disease. Although this study suggests a beneficial effect of adjuvant treatment on survival in patients with PCR, these results are limited by the presence of potential unmeasured confounding in this nonrandomized study.