AIM: To examine the overall survival differences for the following neoadjuvant therapy modalities - no therapy, chemotherapy alone, radiation alone and chemoradiation - in a large cohort of patients with locally advanced rectal cancer. METHOD: Adults with clinical Stage II and III rectal adenocarcinoma were selected from the National Cancer Database and grouped by type of neoadjuvant therapy received: no therapy, chemotherapy only, radiotherapy only or chemoradiation. Multivariable regression methods were used to compare adjusted differences in perioperative outcomes and overall survival. RESULTS: Among 32 978 patients included, 9714 (29.5%) received no neoadjuvant therapy, 890 (2.7%) chemotherapy only, 1170 (3.5%) radiotherapy only and 21 204 (64.3%) chemoradiation. Compared with no therapy, chemotherapy or radiotherapy alone were not associated with any adjusted differences in surgical margin positivity, permanent colostomy rate or overall survival (all P > 0.05). With adjustment, neoadjuvant chemoradiation vs no therapy was associated with a lower likelihood of surgical margin positivity (OR 0.74, P < 0.001), decreased rate of permanent colostomy (OR 0.77, P < 0.001) and overall survival [hazard ratio (HR) 0.79, P < 0.001]. When compared with chemotherapy or radiotherapy alone, chemoradiation remained associated with improved overall survival (vs chemotherapy alone HR 0.83, P = 0.04; vs radiotherapy alone HR 0.83, P < 0.019). CONCLUSION: Neoadjuvant chemoradiation, not chemotherapy or radiotherapy alone, is important for sphincter preservation, R0 resection and survival for patients with locally advanced rectal cancer. Despite this finding, one-third of patients in the United States with locally advanced rectal cancer fail to receive stage-appropriate chemoradiation.