We have found that an immunomodulator, dextran, prevents initiation of tolerance for an unrelated haptenic stimulus of contact hypersensitivity, picryl chloride. To prevent tolerance optimally, 1 to 10 mg of dextran per 25g mouse was required to be injected i.v. 2 hr before administering tolerogen. The immunomodulator was seen to be effective in mice with diverse major histocompatibility backgrounds. Furthermore, prevention of tolerance was seen to be independent of the condition of the hapten used to initiate unresponsiveness, since tolerance was abrogated when attempted with uncoupled hapten or with hapten attached to allogeneic or syngeneic spleen cells. In addition, administering dextran before tolerogen did not convert the tolerogenic signal into an immunogenic one so that hapten-specific DTH could be detected. While the precise mechanism of dextran's interruption of immunologic unresponsiveness for DTH has yet to be elucidated, the principle that tolerance can be readily and easily interrupted with this immunomodulating agent has been firmly established.