Anal squamous cell carcinoma (SCC) is the fourth most prevalent cancer in human immunodeficiency virus (HIV)-infected men who have sex with men (MSM). Human papillomavirus (HPV) has been detected in over 90% of anal carcinoma biopsy specimens from MSM, and is considered a necessary, but alone, insufficient factor for carcinogenesis. Anal intraepithelial neoplasia (AIN) may be precursive for SCC, and screening cytology with referral of persons with abnormality for high-resolution anoscopy-guided biopsy, and AIN treatment, has been recommended for prevention. In the absence of either randomized controlled trials or surveillance data demonstrating a reduction in anal SCC incidence, these recommendations were based on analogy with cervical cancer. HPV-mediated genetic changes associated with cervical cancer, and aneuploidy, have been documented in AIN. However, little data exist on the rate of AIN progression to SCC. The treatment of AIN is frequently prolonged and not curative, and if routinized in the care of HIV-infected MSM, would likely be recurring well into their sixth decade of life. Clinical trials demonstrating a reduction in invasive anal carcinoma incidence, as well as acceptable morbidity with repeated AIN destruction, are needed before asking our patients to commit to routine treatment.