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Abstract Purpose To evaluate efficacy and tolerance of short-course radiotherapy (SCRT) prior to possible chemotherapy (CHT) and surgery in 64 patients with locally advanced rectal cancer, in terms of acute and early late toxicity and survival outcomes with prognostic factors. Methods Sixty-four patients affected by rectal tumor were treated from 2008 to 2023 radiation therapy, with a total dose of 25 Gy in 5 fractions. The Kaplan–Meier method was used to estimate the rates of overall survival (OS), cancer specific survival (CSS), local control (LC), disease free survival (DFS) and metastasis free survival (MFS). Univariate analysis for prognostic factors was performed with the log-rank test, and Cox proportional hazards regression was used to estimate hazard ratios. Toxicity assessment has been considered in acute and in early late for gastrointestinal (GI), genitourinary (GU) districts. Results Median follow-up was 49.6 months. The median OS was 65 months with 1-year, 2-year and 5-year OS at 90.6%, 77.7% and 60% respectively. CSS at the 1-year, 2-year and 5-year was 98.3%, 96.2% and 86.2% respectively. LC at 1-year, 2-year and 5-year was 93.4%, 89.4% and 87.2% respectively. DFS at the 1-year, 2-year and 5-year was 93.4%, 89% and 87% respectively. The status of lymph nodes at diagnosis was a prognostic factor in term of LC and DFS. Acute GI toxicity was G1 in 10 (15.6%) patients. Five (7.8%) patients had a G1 acute GU toxicity. Fifteen (23.4%) patients developed chronic GI toxicities. Conclusions SCRT is an effective treatment in patients with rectal cancer and provides good outcomes with very low rates of toxicity profile.