Bacterial lipopolysaccharide (LPS) was demonstrated to have the capacity in mice to enhance the response to soluble bovine serum albumin (BSA) and to interfere with the induction of tolerance to human γ-globulin (HGG). These adjuvant activities were shown to occur under conditions in which LPS could also function as a B cell mitogen. This positive correlation was established by utilizing two experimental situations in which LPS was non-mitogenic for spleen cells. Thus, on the one hand, it was found that LPS did not function as an adjuvant in C3H/HeJ mice, a unique strain whose spleen cells were also unresponsive to LPS-induced mitogenesis. On the other hand, in strains which did respond to LPS mitogenically, LPS failed to function as an adjuvant when it was chemically altered to reduce its in vitro mitogenic activity. A correlation was also observed between mitogenesis and the capacity of LPS to function as a specific immunogen in mice. In contrast to the sustained and prolonged plaque-forming cell response that was observed in mice whose spleen cells were also responsive to LPS-induced mitogenesis, the response was relatively transient in the C3H/HeJ strain. These results are discussed in view of the possible in vivo modes of action of LPS.