There is a strong association between the incidence of perianal cancer and high-risk human papillomavirus (HPV) subtypes, most notably HPV-16. In contrast, low-risk subtypes, such as HPV-6 and HPV-11, are commonly implicated in the development of condyloma acuminatum or anogenital warts. We present the case of a 40-year-old male patient with a past medical history of hypertension and congenital HIV, which was controlled on highly active antiretroviral therapy (HAART), who presented with a chief complaint of pain at the site of a large fungating perianal mass. A tissue biopsy taken during laparoscopic descending loop colostomy, created to divert stool away from the mass, showed squamous cell carcinoma (SCC) with positive HPV-6 and HPV-11 markers. Following multi-week nutritional optimization, wide local excision (LE) of the tumor followed by immediate plastic reconstruction and closure was performed. The final pathology of the specimen disclosed it as a T4 18 x 17 x 5 cm invasive SCC with moderate differentiation and no lymphovascular invasion. While the association between high-risk HPV and perianal cancer has been well studied and characterized, evidence regarding the development of perianal cancer in the presence of low-risk HPV subtypes is limited to isolated case reports. As a result, there are currently no established guidelines for annual perianal cancer screening in patients with either known low- or high-risk HPV. However, screening does exist for postoperative recurrence of anal and perianal SCC. Due to the increased risk of developing perianal cancer from HPV infection, particularly the high-risk subtype, individualized screening should be emphasized. Overall, further research is needed to develop a standardized protocol that can potentially help reduce the incidence of perianal cancer in high-risk populations with either low-risk or high-risk HPV.