Background and aims: A systematic review was conducted to assess the effects of glutamine, arginine and omega-3 supplementation on the tolerance to treatment, nutritional status and immune function of head and neck cancer (HNC) patients undergoing chemoradiotherapy. Methods: Randomized clinical trials were searched in MEDLINE, EMBASE, CENTRAL, LILACS, ClinicalTrials.gov, OpenGrey and Proquest. Tolerance to treatment, nutritional status, immune function and mortality rate were the primary outcomes investigated. Secondary outcomes comprised functional status, weight loss and body composition. Risk of bias of individual studies and the overall quality of the evidence were assessed using the Cochrane and the GRADE tools, respectively. Results: Nineteen articles met the inclusion criteria and nine were included in the meta-analyses, which assessed mucositis severity, weight loss and handgrip strength. Ten studies were evaluated as high risk of bias. Glutamine supplementation has significantly reduced the risk of grade 2-4 mucositis (RR: 0.76, IC95% [0.63; 0.92], P = 0.006, I2 = 0%; P = 0.792; 4 studies). Omega-3 supplementation did not show statistically significant results on weight loss (SMD: -0.042, 95% CI [-0.322; 0.238], P = 0.769, I2 = 33.4%; P = 0.212; 4 studies). The overall quality of the evidence ranged from low to very low. Conclusions: These results must be interpreted with caution due to differences between supplementations regimen, lack of methodological rigor in most studies and due to the possible role of glutamine in tumor metabolism. Studies focused on elucidating the contribution of each immunonutrient to HNC patients undergoing chemoradiotherapy deserve further investigation. Keywords: Arginine; Chemoradiotherapy; Fatty acids; Glutamine; Head and neck neoplasm; Immunomodulation; Omega-3.