The binding of cryptococcal polysaccharide to a non-encapsulated strain of Cryptococcus neoformans was studied. Binding of purified polysaccharide to the yeast was determined by inhibition of phagocytosis and by indirect immunofluorescence techniques. The ability of cryptococcal polysaccharide to prevent phagocytosis of the non-encapsulated strain appears to be directly related to adherence of polysaccharide to the yeast via specific receptors on the cell surface. Addition of varying doses of cryptococcal polysaccharide to non-encapsulated yeast cells inhibited phagocytosis only at polysaccharide concentrations at which the polysaccharide could be demonstrated on the yeast surface by immunofluorescence. Macrophages treated with cryptococcal polysaccharide had no detectable amounts of cryptococcal polysaccharide adherent to their surface, and they had a normal ability to phagocytize the yeast. Kinetic studies showed that inhibition of phagocytosis is directly related to the presence of cryptococcal polysaccharide at the yeast surface rather than to some indirect effect by the polysaccharide on serum components necessary for phagocytosis. Purified polysaccharide from C. neoformans serotypes A, B, C, and D bound to the yeast, but type III pneumococcal polysaccharide did not inhibit phagocytosis of the nonencapsulated yeast. Cryptococcal polysaccharide did not bind to cells of Candida albicans, C. pseudotropicalis, Torulopsis sp., Rhodotorula sp., or Saccharomyces cerevisiae.