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Background: Recently, many studies have suggested a possible adjuvant role of aspirin in colorectal cancer, reporting a positive prognostic effect with its use in patients with established disease. The aim of this study was to investigate the anticancer effect of aspirin use during preoperative chemoradiation for rectal cancer., Methods: Two hundred and forty-one patients with stage II-III rectal cancer and candidates for chemoradiation (CRT) were selected and assigned to two groups: group 1, patients taking aspirin at the time of diagnosis, and group 2, all others. Treatment and oncological outcomes were explored., Results: Aspirin use was associated with a higher rate of tumour downstaging (67.6% vs 43.6%, P=0.01), good pathological response (46% vs 19%; P<0.001), and a slightly, although not significant, higher rate of complete pathological response (22% vs 13%; P=0.196). Aspirin use was also associated with a better 5-year progression-free survival (86.6% vs 67.1%; hazard rate (HR)=0.20; 95% CI=0.07-0.60) and overall survival (90.6% vs 73.2%; HR=0.21; 95% CI=0.05-0.89). Although chance of local relapse was similar (HR=0.6; 95% CI=0.06-4.5), aspirin use was associated with a lower risk of developing metastasis (HR=0.30; 95% CI=0.10-0.86)., Conclusions: Aspirin might have anticancer activity against rectal cancer during preoperative CRT. This finding could be clinically relevant and should be further investigated with randomised trials.