The present study was undertaken to evaluate the effect of phagocytosis of killed yeast on the induction of apoptosis in human metastatic breast cancer cells (MCF-7 and ZR-75-1) and non-metastatic breast cancer cells (HCC70). Heat-killed Saccharomyces cerevisiae, baker's and brewer's yeast, was cultured with cancer cells at a ratio of yeast to cancer cells = 10:1, and the percent apoptotic cancer cells was determined by flow cytometty and cytospin preparation. Upon phagocytosis of yeast, breast cancer cells underwent apoptosis. Induction of apoptosis was time- and dose- dependent. Apoptosis was detected as early as 0.5 h (13%), increased to 19% at 2 h and peaked (38%) at 4 h. Metastatic cancer cells were found to be more susceptible to yeast-induced apoptosis than non-metastatic cells; 629% increase for MCF-7 as compared to cells alone, 258% for ZR- 75 cells, while HCC70 cells showed a 178% increase. Phagocytosis is associated with the disruption of mitochondrial membrane potential and activation of initiator and effector caspases 8, 9 and 3. However, inhibitors of these caspases did not inhibit yeast-induced apoptosis in cancer cells, suggesting that yeast induces apoptosis in breast cancer cells by a mechanism that is independent of caspase activation. This data may have clinical implications.