Background: The survival rate for patients with locally advanced high-risk squamous cell cancer of the head and neck has not substantially improved in recent years. There is a strong need for effective preventive approaches to reduce the incidence of relapses, second cancers and treatment-related late sequelae. Aims: a specific dietary intervention as an economic and non-toxic method to reduce the risk of relapse, widely and easily accessible in all EU countries; the potential identification of reliable biomarkers associated with dietary efficacy. Methods: The study recruited, from 5 different European cancer centers, 100 patients, disease-free after curative treatment, who were randomized into an experimental arm (highly monitored and specific dietary intervention and AICR/WCRF recommendations for cancer prevention) and in a control arm with dietary recommendations only. Patients were monitored at baseline and after 6, 12, 18 and 24 months for disease course and late toxicity; quality of life and nutritional questionnaires and biological samples (levels of circulating cytokines, miRNAs and salivary microbiota) were collected at each visit. Results: At baseline, we can conclude that: 1) the analyzes obtained for the clinical and translational endpoints were feasible in 75% and 67% of the enrolled patients and the data obtained were informative; 2) the two arms did not differ in clinical characteristics (HPV status, smoking, tumor site, TNM stage), quality of life and nutritional status; 3) miRNA and microbiota profiles tended to be associated with body mass, but not with ARMs. As for the follow-up, about 50% of questionnaires and biological samples are available for each time point and the analyses are in progress. Conclusions: Based on the comparisons of adherence to diet (according to the questionnaires) and of levels of biological markers and after the integration of the results, we expect to define whether dietary intervention alone is able to improve the quality of life and outcome of patients and if this trend could be monitored by circulating biomarkers.