Anal cancer is a rare disease with an increasing incidence worldwide but, unfortunately, even today the scientific community still has a limited knowledge and limited options of treatment.

More than 50% of patients with anal cancer presenting at diagnosis with locoregional disease have good chances of cure with chemoradiotherapy (CT–RT). However, once patients develop metastatic spread, the prognosis is very poor.

Human papillomavirus (HPV) is present in more than 80% of anal cancers and while multiple etiologic connections between HPV infection and anal cancer have already been well elucidated, its prognostic and/or predictive role is currently under investigation, especially among immunocompetent patients affected by this disease.

In a single-institutional set, we have retrospectively analysed clinical data of 50 consecutive cases homogeneously treated with CT–RT for stage I–III anal squamous cell carcinoma. We found that HPV-positive anal cancers had a statistically significant improved five-year disease-free survival (DFS) compared to HPV-negative group. These findings could be explained by an increased chemo/radiosensitivity of HPV-positive tumours. Further efforts should be directed towards a better understanding of HPV-related oncogenesis and towards designing novel tailored strategies for the management of this disease both in terms of prevention and treatment.