Degradation of the mucus layer by Entamoeba histolytica is a prerequisite for invasion of the colonic mucosa. In this study, we demonstrate that amoeba-secreted products degrade (3)H-labeled and native colonic mucin oligosaccharides independently of proteolytic activity. We conclude that E. histolytica degrades mucin oligosaccharides, which may facilitate parasite invasion of the colon.