Background: Neoadjuvant short-course (SC) radiation (RT) followed by fluoropyrimidine based chemotherapy prior to surgery (Polish II approach) is a less utilized treatment in the United States for rectal cancer. Based on data suggesting equivalent or improved outcomes at lower cost compared to the long course neoadjuvant chemoradiation, our team started utilizing this approach for rectal cancer management at Simmons Comprehensive Cancer Center. We aim to document our experience with Polish II approach at NCI-designated comprehensive cancer center program. Methods: A retrospective review of stage I-IV rectal cancer patients, seen at an academic center or the Dallas County safety net hospital and treated at Simmons Comprehensive Cancer Center from Nov 2017 to Dec 2019. Patients were treated with neoadjuvant SC-RT followed by 3 cycles of FOLFOX prior to surgery and followed by adjuvant FOLFOX. Descriptive data for demographic, radiation, chemotherapy and surgery, hospitalizations, 30 day post-surgery admission, time to relapse, and laboratory parameters was collected. Results: Thirty-nine patients met the inclusion criteria (average age 58 years; 74% men/26% women). Forty-six percent of patients were Hispanic, 28.2% White, 15.4% African American and 7.7% Asian. The majority of patients had stage IIIB (46.2%), followed by IIIC (17.9%), IIA (12.8%), IIIA (7.7%), while rest were stage I, IVA or unknown (5.1%). All patients received 5 x 5 SC-RT, 100% completed 3 cycles of planned neoadjuvant FOLFOX (12.8% received 4-8 cycles) and 36/39 (92%) of patients underwent planned surgery. Median duration from SC-RT to chemotherapy was 12 days, and from chemotherapy to surgery was 37 days. Hospitalization occurred in 3 patients (7.7%) during neoadjuvant therapy, and in 8 patients (20.5%) within 30 days post-surgery. Complete pathological response was seen in 6 patients (16.6%) and near-complete pathological response in 3 patients (8.3%). Relapse occurred in 10.3% patients at time of data acquisition. Grade 3 and 4 neutropenia, anemia, and thrombocytopenia in neoadjuvant phase was observed in 8.6%, 25.7%, and 2.8% patients, respectively. Conclusions: In rectal cancer patients treated at a comprehensive cancer center, neoadjuvant Polish-II approach was feasible and well tolerated. Pathological response rates were comparable to historical data. SC-RT based neo-adjuvant therapy approach should be favored due to lower pelvic radiation dose, tolerance and convenience to patients.