ObjectiveIn this study, we aimed to describe the prospective implementation of the Enhanced Recovery after Surgery (ERAS) protocol in an Italian tertiary academic centre. MethodsAdult patients receiving surgery for primary or recurrent clinical stage III/IV squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx were enrolled. The primary objective was to evaluate the impact of the ERAS protocol on length of hospital stay (LOS). The secondary objective was to assess its impact on complications. To evaluate the results of the ERAS protocol, a matched-pair analysis was conducted, comparing ERAS patients with comparable cases treated before 2018. ResultsForty ERAS and 40 non-ERAS patients were analysed. There were no significant differences between the cohorts regarding age, gender, stage of disease, comorbidity, ASA score, and duration of surgery. A significantly shorter LOS for the ERAS group (median, 14 days; range, 10-19) than for non-ERAS patients (median, 17.5 days; range, 13-21) was observed (p = 0.0128). The incidence of complications was not significantly different (p = 0.140). ConclusionsOur study demonstrates that the introduction of an ERAS protocol in the daily practice is feasible, and can result in significant reduction in LOS.