Background Information is lacking regarding anal/perianal precancerous lesions in referral cohorts of pharmacologically immunocompromised patients. Objective The aim of this study is to evaluate the prevalence of anal/perianal high-grade squamous intraepithelial lesions in a referral cohort of patients on immunomodulator/immunosuppressive medications, who were assessed and followed with high-resolution anoscopy. Design This is a retrospective study. Setting This study was conducted in a single anal neoplasia service from January 2012 to June 2017. Patients Patients on chronic immunomodulator/immunosuppressive medications were included. Cases of concomitant immunosuppression due to HIV infection were excluded, and immunosuppression due to chemotherapy was not considered for this analysis. Intervention High-resolution anoscopy was performed. Main outcome The primary outcome measured was the prevalence of anal/perianal high-grade squamous intraepithelial lesions in a referral cohort of pharmacologically immunocompromised patients. Results Fifty-four patients were included, of whom 40 were women (74%), with a mean age of 48 ± 17 years. A total of 232 high-resolution anoscopy examinations were performed in this cohort. At the first evaluation, 28 patients (52%) were diagnosed with anal and/or perianal high-grade squamous intraepithelial lesions (including 2 cases of perianal squamous cell carcinoma); 11 cases (20%) were new diagnoses. Ten of 46 patients (22%) with follow-up developed a new lesion (high-grade/cancer) during a median follow-up period of 17 (interquartile range, 6-28) months. Overall, 37 patients (69%) in our cohort had anal/perianal high-grade squamous intraepithelial lesions ever diagnosed (including previous history, first visit, and follow-up); 5 patients had perianal squamous cell carcinoma. At our center, 6% of the new referrals were known to be pharmacologically immunocompromised patients. Limitations The retrospective nature of this study, the heterogeneity of the cohort, and the absence of human papillomavirus testing were limitations of this study. Conclusions The presence of anal and/or perianal high-grade squamous intraepithelial lesions or cancer detected by high-resolution anoscopy in this referral population was high, and the detection of new lesions suggests that long-term follow-up is needed. Patients on immunomodulator/immunosuppressive drugs represented only a small percentage of the new referrals to our center. See Video Abstract at http://links.lww.com/DCR/A748.