Background: Hypofractionated short course radiation treatment (SCRT) as part of a total neoadjuvant treatment (TNT) approach to treat rectal cancer has increased in popularity since the publication of the RAPIDO trial. However, the literature on SCRT for rectal cancer has not reported significant acute toxicities in the weeks immediately following the completion of treatment. This study examines the acute toxicities in patients treated with hypofractionated radiation therapy as part of their definitive treatment for rectal cancer. Methods: At our institution, we retrospectively analyzed 71 patients with locally advanced rectal cancer treated between 2016-2022 with SCRT (25 Gy in 5 fractions) as part of definitive treatment. Acute toxicity caused by radiation was defined as that occurring from the start of radiation treatment to either 30 days post radiation completion, the start of chemotherapy, or date of surgery, whichever occurred first. Acute neuropathic lumbosacral (LSN) pain was defined as bilateral radiating pain down the lower extremities. Matched patients without reported LSN pain were identified and matched on N stage, location of tumor, and treatment position. Organs at risk were contoured on the CT planning scan and dosimetric analysis was conducted on the patient’s treatment plan. Results: In 71 patients treated with SCRT, we identified diarrhea (n=34, 47.9%), rectal pain (n=15, 21.1%), rectal urgency (n=15, 21.1%) nausea (n=14, 19.7%), and rectal bleeding (n=12, 16.9%) as frequent acute toxicities in the setting of SCRT. For patients with rectal pain, 31.2% required steroids. We also identified an acute toxicity of LSN pain in 10 patients (14.1%). Patients rated this LSN pain between moderate and severe; median time to LSN pain was 2 days (range 1-6 days). For LSN pain, management was conservative for 3 (30%) patients and symptoms self-resolved. The other 7 patients required ibuprofen and acetaminophen treatment; 2 of these patients had persistent symptoms and one was treated with topical hydrocortisone and gabapentin and the other with a burst of methylprednisolone. Dosimetric analysis of the lumbosacral nerve plexus area did not detect a statistically significant difference in dose parameters between symptomatic and asymptomatic patients. Conclusions: We have identified acute toxicities in patients treated with short course hypofractionated radiation, including diarrhea, rectal pain requiring steroid treatment, and previously underappreciated neuropathic lumbosacral pain. Toxicities mainly occurred within one week of treatment and resolved. Further analysis will seek to identify predictive factors of these acute toxicities and to determine whether there is a correlation between these observed acute toxicities and long-term outcomes.