Summary Background & aims Malnutrition is frequent in head and neck (HN) and esophageal cancer patients and aggravated by radiochemotherapy (RCT), increasing morbi-mortality and treatment toxicity. Our goal was to investigate the effect of immunonutrition consisting of an arginine, omega-3 fatty acid, nucleotides-enriched diet on nutritional status, and functional capacity in HN or esophageal cancer patients undergoing RCT. Methods 37 patients were randomized in a double-blind clinical trial. 5 days before and until the end of RCT (5–7 weeks), they received either an Immunomodulating Enteral Nutrition (IEN) or an isonitrogenous, isoenergetic Standard Enteral Nutrition (SEN). Anthropometrical parameters, nutritional risk index (NRI), serum albumin, plasma antioxidant capacity, and functional capacity were recorded between the beginning and the end of RCT. Results A significant gain in total body weight (+2.1 ± 3.1 kg) was observed in IEN patients. Albuminemia and NRI were improved concomitantly in IEN malnourished patients. Plasma antioxidant capacity was improved (+100 ± 13 μM Eq Trolox) in IEN patients. Functional capacity measured by WHO Performance Status and Karnofsky index was maintained in IEN patients but significantly reduced in SEN patients. Conclusions These preliminary data show that immunonutrition could improve the nutritional status together with functional capacity in HN and esophageal cancer patients undergoing RCT. Clinical trial registration This clinical trial promoted by the University Hospital Center of Clermont-Ferrand has been registered at ClinicalTrial.gov website under the following reference: NCT00333099.