Background: Cisplatin(DDP)-based chemoradiation (CCR) is currently used to treat locally advanced head and neck squamous cell carcinoma (LAHNSCC), either as an exclusive modality or in the adjuvant setting. Acute, treatment-related toxicities are frequent. In this prospective cohort study, we evaluated the impact of patient (pt) navigation in multidisciplinary care by nurses on adherence to consultations and procedures, number and duration of hospital admissions, admissions to the emergency department, and treatment-related toxicities. Methods: In this prospective, uni-institutional cohort study, pts diagnosed with LAHNSCC (oral cavity, oropharynx, hypopharynx, and larynx) were consecutively included at the beginning of CCR, after informed consent. The navigation program included: (1) referral to multidisciplinary care (Nutrition, Psychology, Social Work); (2) monitoring attendance at multidisciplinary clinical visits; (3) monitoring of possible hospital and emergency admissions; and (4) diagnosis and monitoring of treatment-related toxicities, graded according to CTCAE v5.0. To observe an effect size of 0.50 with a power of 80% and a type I error of 0.05, 64 pts would be needed. Here we present the analysis of the first 26 pts included, with outcomes compared to 130 LAHNSCC pts treated with CCR at the same institution in 2019. Accrual was stopped. Results: 26 pts were included between Mar/2021 and Sep/2021, with a median age of 57 years, being 77% men, with KPS ≥ 80% in 25 pts (96%), and with a primary tumor in the oral cavity or oropharynx in 18 patients (69%). CCR was administered in the adjuvant setting in 9 pts and as an exclusive treatment in 17 pts. 10 pts (39%) experienced DDP discontinuation (mainly for toxicity) in the navigation group, compared to 67% in the control group (p = 0.008); and the duration of radiotherapy was 48d and 49d, respectively (p = 0.483). No grade 4 adverse events were observed in navigated pts. The median number of absences (any visit or treatment) was 1.0 (control) and zero (navigation, p < 0.001). Admission to the emergency department occurred in 6 navigated pts (23%) as compared to 100 control pts (77%, p < 0.001), while hospitalizations occurred in 1 (3.8%) and 50 (38.5%, p < 0.001), respectively, lasting 4.9±9.7d and 1±0.39d (p = 0.001). Conclusions: The navigation program provided better outcomes in comparison to the control group, in terms of a lower number of missed appointments, a higher number of chemotherapy cycles administered, lower frequency of severe toxicities, lower frequency of attendance at emergency and hospitalization services, as well as reduced length of hospital stay.