The increasing incidence of HPV-related oropharyngeal squamous cell carcinoma (OPSCC) observed in several developed countries has not yet been documented in Italy. To investigate changes in the epidemiology of HPV-related OPSCC we reviewed the HPV status of cases evaluated at our centre in northern Italy before and after 2010. The results were correlated with patient age, sex, oropharyngeal subsite (classified as palatine tonsil, tongue base, palatine arch/palate/uvula, posterior oropharyngeal wall, and oropharynx not otherwise specified), AJCC tumour stage, risk factor exposure (smoke, alcohol), disease history (recurrence, metastasis, second tumours), outcome and survival. Positivity for p16 and HR HPV DNA was required to classify HPV-related OPSCC. HPV-related tonsillar OPSCC increased significantly after 2010, while a non-significant reduction of HPV-related extra-tonsillar OPSCC was observed. Non-keratinising morphology was strongly associated with HPV positivity. HPV16 was the most common genotype; the frequency of other high-risk genotype infections decreased after 2010. At multivariate analysis, HPV status showed a significant association with better outcome. We documented an increase of HPV-related OPSCC in our Italian population, synchronous with the increase observed in several Western countries, which in recent years reached a prevalence similar to that reported in central European countries. Our results indicate that HPV infection in head and neck oncology is relevant in Italy and needs to be considered for accurate patient stratification.