The effects of Salmonella endotoxin and staphylococcal enterotoxin B (SEB) were examined in vitro on mouse and human lymphocyte populations from unsensitized subjects. These substances were found to be extremely stimulatory to mouse spleen cells as measured by 3H-thymidine incorporation. In regards to size, general morphologic features, and staining properties, the cell cultures appear identical to cultures stimulated by phytohemagglutinin (PHA). However, endotoxin failed to stimulate human peripheral lymphocytes while PHA and SEB produced a response over a wide dosage range. Attempts to detect stimulation of human lymphoid cells by endotoxin using various mammalian sera as augmentors were unsuccessful.