Background: Pre-clinical evidence suggest that statins have antiproliferative, proapoptotic, and anti-invasive properties. Also, statins can sensitize cancer tissues and protect normal tissues to the effects of radiation. A standard treatment of locally advanced rectal cancer (LARC) involves neoadjuvant CRT followed by surgery and adjuvant chemotherapy. Retrospective analyses of statin use in rectal cancer patients receiving CRT suggest a higher pathological complete response rate (pCRr). Methods: Patients with clinical stage II-III rectal adenocarcinoma, within 5 cm of the anal verge (AV) or less than 12cm from the AV with threatened circumferential resection margin were treated with rosuvastatin 40 mg daily starting 2 weeks prior to the start and until 4 weeks after the end of CRT. The primary objective of the study was pCRr. Secondary objectives included, near-CRr, Ro resection rate (RR), sphincter preservation, 3-year relapse free survival (RFS), 3-year overall survival (OS), toxicity and safety. A Simon’s minimax two-stage design was used to determine significance. A pCRr of ≥25% was required to reject the null hypothesis. RFS and OS rates were calculated using the Kaplan-Meier product-limit method. Results: Forty-five patients were enrolled from 2016 to 2021. Sixty-seven percent were male with a median age of 54 (IQR 37- 61), 97.8% (44/45) had ECOG PS of 0-1, 15.6% (7/45) were cT4, 73.3% (33/45) were cN+. Of the 38 evaluable patients, 9 had a pCR (23.7%), an additional 9 had a near-pCR (23.7%). With a median follow-up of 3.26 years, the 3-year OS rate was 96.3% (95% CI (0.765, 0.995)) and the 3-year DFS rate was 77.9% (95% CI (0.604, 0.883)) in the evaluable patients. One patient elected for non-operative management and has an on-going clinical CR for the last 15 months. Surgery was sphincter sparing in 17 patients (43.6%) and an 87.2% Ro RR was observed. Toxicities attributable to rosuvastatin included: two patients with elevations in liver enzymes, grade 3. Remaining toxicities were grade 2 or less, with the most common toxicities being fatigue (n = 5) and pain (n = 3). Only 2 patients experienced CPK elevations, both grade 2. Conclusions: The addition of rosuvastatin to nCRT resulted in a considerable complete and near-complete response rate with an acceptable toxicity profile. Rosuvastatin treatment should be studied further in the total neoadjuvant and non-operative management settings for locally advanced rectal cancer. Clinical trial information: NCT02569645.