During the immune response to H-2 and Mls alloantigens, murine lymphocytes showed altered sensitivity to polyclonal mitogens. The reactivity to the T-cell mitogen PHA followed a similar pattern in both H-2 and Mls-immunized mice while the reactivity to the B-cell mitogen LPS was contrasting in the two groups. In the former group, the response exceeded control levels by the seventh day after immunization and then gradually dropped below control levels; the response of Mls-immunized lymphocytes dropped below control levels soon after immunization and remained so for the period of study. Nylon wool column-purified Mls-immunized B cells also showed a suppressed reactivity to LPS, while the T-enriched populations from Mls-immune mice when added to normal B cells lowered their LPS reactivity. Soluble factors derived from clutures of Mls-immune lymphocytes had a suppressive effect on normal B cells.