Human papillomavirus (HPV) infection is linked to the development of cervical cancer, and several cofactors contribute to the risk of disease. Research on the intratypic variability of HPVs has defined variants that are associated with persistent infections and are potentially more oncogenic, translating to a higher risk of malignant disease. The genetic variability of the host also plays a role in the risk of cervical cancer, especially genes controlling the immune response, such as HLA class I and II. These highly polymorphic genes are important risk determinants of HPV persistence and disease progression. The interaction between host and viral factors is complex and needs to be further investigated, paving the way to better define the patients at the highest risk of developing malignant diseases linked to HPV infection.