The aim of our study was to assess the overall trends in the incidence of head-and-neck cancer (HNC) among Danish men and women in 1978-2007, to describe the distribution and incidences of HNCs at different anatomical sites, and to determine whether the incidence of human papillomavirus (HPV)-associated cancers is increasing. Data were extracted from the nationwide Cancer Registry database. To assess the possible impact of HPV infection, the sites of squamous cell carcinomas were categorized as HPV-associated, potentially HPV-associated or HPV-unrelated. In total, 26,474 incident cases were identified and the overall incidence increased throughout the period. Significantly increasing incidence rates were notably seen for tumors in the oral cavity (2.2% per year), tonsils (4.8% per year), oropharynx (3.5% per year) and hypopharynx (4.4% per year). A significantly decreasing incidence of lip cancer was observed among men (-5.0% per year). Cancers at HPV-associated sites (n = 3650) showed strongly increasing incidence rates, primarily in individuals < 60 years. In contrast, HNCs at sites not related to HPV infection showed a significant decrease (in men) or virtually no change in incidence (in women). Our results suggest a marked impact of HPV infection on the epidemiology of HNCs in Denmark. HPV16 is the type most often found in HNCs; thus, the recent introduction of vaccination against HPV may in the future prevent HPV-associated cancers of the head and neck.