Rodent natural killer (NK) lymphocytes are cytotoxic to certain fungi. We investigated whether human NK cells are cytotoxic to the yeast Candida albicans. We found that human peripheral blood lymphocytes possessing NK cell activity had little or no effect on the viability of the yeast. Unopsonized C. albicans, however, were able to block NK cell-mediated cytotoxicity at a ratio of 100 yeast to one K562 erythroleukemia cell. C. albicans was not toxic to the lymphocytes nor did it take up isotope released by the K562 cells. Furthermore, C. albicans that was pretreated with human serum blocked NK cell activity more than did untreated C. albicans. Binding of the yeasts to NK cells could account for the blocking effect of serum-treated yeasts, but not for that of the untreated yeasts. Flow cytometry indicated that there was preferential binding of C. albicans to NK lymphocytes but not to T cells when the yeasts were pretreated with human serum. In this report we affirm the results of the study by Vecchiarelli et al. (A. Vecchiarelli, F. Bistoni, E. Cenci, S. Perito, and A. Cassone, Sabouraudia 23:377-387, 1985), that the first report of rodent NK cell activity against the yeast Cryptococcus neoformans (J. W. Murphy and D. O. McDaniel, J. Immunol. 128:1577-1583, 1982) cannot be extrapolated to a general phenomenon of unprimed lymphocyte-mediated destruction of all species of yeast. Our data extend the observations to humans and also suggest that in vivo interactions between NK lymphocytes and opportunistic fungal pathogens may affect NK cell function.