The aim of our study was to determine the baseline prevalence of anal squamous intraepithelial lesions (SIL) and associated risk factors in HIV-infected men who have sex with men (MSM) in a Spanish ongoing multicenter cohort. CoRIS-HPV started in 2007, nested in the Spanish AIDS Research Network Cohort (CoRIS). Anal liquid cytology testing was performed. High-risk human papillomavirus (HR-HPV) infection was determined, and positive samples were genotyped. We analyzed all subjects up to April 2011. Multivariate logistic regression analyses were performed. A total of 551 subjects with baseline anal liquid cytologies were analyzed; 37.0% negative for intraepithelial lesion, 9.0% atypical squamous cells of uncertain significance (ASCUS), 41.0% low-grade SIL, 4.0% high-grade SIL and 9.0% inadequate. Prevalence of anal SIL (excluding ASCUS) in valid samples (n = 450) was 54.7% (95% confidence interval [CI] = 49.9–59.3). Globally HR-HPV prevalence was 81.7% (95% CI = 78.0–85.2). Multiple infections (≥2 HR-HPV genotypes) were documented in 77.7% (95% CI = 73.1–82.0). The only risk factor associated with anal SIL was the number of HR-HPV types; MSM with five or more HR-HPV genotypes had an odds ratio (OR) of anal SIL seven times greater (OR = 7.4; 95% CI = 2.8–19.6) than those with one HR-HPV genotype. No associations were found for age, educational level, smoking, geographical origin, CD4 T-cell count, antiretroviral treatment or number of sexual partners. The prevalence of anal SIL in young HIV-positive MSM is high, and the main risk factor is multiple infections with HR-HPV types.