Abstract We have studied the effects of yeast cell wall derivatives (zymosan and particulate β-glucan), on the cytolytic effector function of human natural killer cells. Both zymosan and particulate β-glucan were found to inhibit the NK-cell-mediated killing of K562, Molt-4, U937, and HL60 tumor cells. Zymosan also inhibited the IL-2-dependent proliferation of NK cells, suggesting that some component of the yeast cell wall delivers a down-modulatory signal affecting multiple NK cell functions. NK cell surface molecules capable of binding both zymosan and Sepharose-immobilized pustulan (linear 1,6-β-D-glucan, a carbohydrate component of zymosan and particulate β-glucan) were identified in detergent lysates prepared from surface iodinated NK cells. Our results suggest that NK cells express cell surface β-glucan-binding lectins that may contribute to NK-cell-mediated natural cytotoxicity.