Human papillomaviruses (HPVs) are the causative agent of cervical cancer, and among approximately 15 high-risk genotypes, HPV16 accounts for more than half the cases of cervical cancer worldwide. Recent progress in determining HPV genomic sequences from clinical samples has revealed a wide variety in HPV16 genome sequences, and has allowed for comprehensive classification of intratype HPV16 variants. These consist of four variant lineages containing nucleotide variations in 1.0%–10.0% of the complete viral genome sequence. Epidemiological data suggest that the non-European–Asian lineages of HPV16 entail a higher risk of progression to invasive cervical cancer than the European–Asian lineage. Deep sequencing analysis has recently demonstrated that HPV16 genome sequences are highly homogeneous in individual clinical specimens compared with those of RNA viruses. However, an extremely sensitive PCR method, differential DNA denaturation PCR, has detected hypermutations from C to T or G to A in the E2 gene and the long control region of the HPV16 genome, which suggests the involvement of cellular apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) proteins in this hypermutation. The quasispecies status of the HPV16 genome in the infected cervix may affect the development of cervical cancer and warrants further investigation.