Preclinical studies have demonstrated carrageenan's anti–human papillomavirus (HPV) activity. We assessed efficacy of a carrageenan-based gel compared to a placebo gel in increasing the clearance of anal HPV infections among gay, bisexual, and other men who have sex with men (gbMSM). Of 255 enrolled gbMSM, 134 were HPV positive at baseline and had valid HPV results for ≥2 visits. Carrageenan did not differ from placebo in clearing all baseline infections (hazard ratio, 0.84 [95% confidence interval,.31–2.27]), based on having 2 consecutive HPV-negative visits following at least 1 HPV-positive visit. There were no remarkable differences for analyses at the HPV type level or by human immunodeficiency virus status. Clinical Trials Registration NCT02354144. [ABSTRACT FROM AUTHOR]