Aim To retrospectively evaluate the potential impact of statin and aspirin use on acute toxicity and pathological complete response (pCR) rate in rectal cancer patients receiving neo-adjuvant long-course radiation therapy (LCRT) with concurrent chemotherapy. Methods A retrospective review was performed of all patients undergoing neo-adjuvant LCRT for rectal adenocarcinoma at the Regional Cancer Treatment Service between 1 September 2007 and 1 June 2011. Data obtained include demographic details; date and radiological TNM stage at diagnosis; medication taken at time of RT; toxicity during LCRT; and surgical histology to determine if a pCR was obtained following LCRT. Results Neo-adjuvant LCRT was administered to 142 patients for rectal cancer during this period; concurrent chemotherapy was omitted in 13 due to significant comorbidities. TNM stage was 2 or 3 radiologically at diagnosis in 127 (89.4%) of patients. At the time of LCRT, 23% were taking a statin and 25% were taking aspirin. Of 135 assessable patients, 34 (13%) achieved a pCR at surgery. On logistic regression, pCR was not significantly associated with the use of chemotherapy, statins, aspirin, other NSAIDs, T-stage or N-stage. There was no significant correlation between statin or aspirin use with bladder or rectal toxicity. Actuarial time to maximum rectal toxicity was not different in statin users or nonusers. Conclusion In contrast to other larger retrospective series, this study did not find improvements in toxicity or pCR rate through statin or aspirin use in rectal cancer patients undergoing LCRT. Their potential benefits in this setting would be best studied prospectively in a large randomized trial.