The second factor that has resulted in a paradigm shift in understanding the etiology of anal cancer is the discovery that the human papilloma virus (HPV), especially HPV serotypes 16 and 18, 5 is the primary cause of squamous cancers of the anus, 6, 7 making anal cancer a sequela of a sexually transmitted disease. This aspect of anal carcinogenesis reinforces the concept that it is a potentially preventable disease and that if evidence-based screening and preventative measures were developed and consistently applied, decreases in cancer-related deaths would follow. The modifiable risk of death from anal cancer is further underscored by large studies that have documented that≈ 50% of patients with anal cancer present with localized, node-negative disease, which is associated with high cure rates; one third of patients will present with node-positive disease, whereas only 10% to 15% will present with distant metastases. 8 Thus, even without effective preventative measures, the majority of patients with anal cancer are potentially curable at the time of diagnosis and treatment. The multiple risk factors associated with developing squamous cancers of the anus are well documented and can be grouped into the 2 broad categories of HPV and immunosuppression, although there is also an association between these categories as well. Among the HPV-related risk factors include lifetime number of sexual partners, 9 a history of previous sexually transmitted diseases of any kind, 10 a history of anogenital warts, 11 anoreceptive intercourse, 12 and a history of cervical, vaginal, or vulvar cancer. 13 Risk factors related to immunity include a diagnosis of HIV, 14 autoimmune disorders such as lupus and sarcoidosis, 15 and being the recipient of a solid organ transplant. 16 Female sex3 and cigarette smoking17 are also associated with developing anal malignancies.