Glutamine is a nutraceutic with antioxidant and immune functions that can protect from adverse effects associated with radiation therapy (RT). The aim of this study was to test whether oral glutamine prevents oral mucositis (OM) or acute radiation-induced esophagitis (ARIE) and favors nutritional status. This retrospective, cohort study included patients treated with RT for cancer on head and neck (HN) or chest areas during the 2008-2010 period. Data on glutamine treatment (initiated before RT, during RT, or no glutamine), appearance of mucositis (according to World Health Organization criteria), weight loss (WL) during RT, moderate [body mass index (BMI) <20.5 kg/m(2) or WL > 5%) or severe (BMI < 18.5 kg/m(2) or WL > 10%) malnutrition, and nutritional support were collected. Quantitative data were compared using Student's t-test and analysis of variance, and qualitative data using the chi-square test. The risk difference was calculated with its 95% confidence interval (95% CI). The sample included 117 patients. Overall, glutamine was associated with a significant reduction of mucositis, WL, and enteral nutrition. The risk difference for developing OM in patients receiving glutamine when compared with controls was -9.0% (95% CI = -18.0% to -1.0%), and for ARIE it was -14.0% (95% CI = -26.0% to -1.0%). More of the patients not receiving glutamine developed severe malnutrition when compared with those receiving this supplement, but there were no differences in other outcomes such as interruption of RT, hospitalization, use of opioid analgesics, or death during RT. Glutamine may have a protective effect during RT, reducing the risk and severity of OM and ARIE, preventing weight loss, and reducing the need for nutritional support. Prospective trials are required.