Candida albicans hydrophilic yeast cells specifically adhere to mouse macrophages in the splenic marginal zone and in lymph node subcapsular and medullary sinuses. These macrophages express sialoadhesin that binds erythrocytes, but binding of yeast cells is not mediated by sialoadhesin because (i) erythrocytes did not block yeast cell binding, (ii) yeast cell adherence was unaffected by sialoadhesin-specific monoclonal antibodies, (iii) the purified sialoadhesin did not bind to yeast cells, and (iv) an Fc-sialoadhesin chimera immobilized on plastic did not bind yeast cells. These data give further support for a unique macrophage adhesion system that binds C. albicans.