The H-2 restriction imposed on the T-lymphocyte-macrophage interaction leading to the expression of acquired cellular immunity was evaluated in an experimental model of infection with the live vaccine strain of Francisella tularensis. Restriction between T cells and macrophages was examined in vitro in cultures containing macrophages from C57BL/10 (B10) mice, T cells from immune B10 H-2 congenic mice, and F. tularensis antigen. The cellular interaction was assayed by the production in the cultures of factors which stimulate thymocyte DNA synthesis. It was observed that homology at the I-A region of the H-2 complex was required for productive T-cell-macrophage cooperation to occur. Restriction was also investigated in an in vivo passive cell transfer system. Spleen cells from immunized B10 mice were injected into naive B10 H-2 congenic mice, which were then challenged with F. tularensis. Enhanced resistance to the challenge infection in recipient mice was used as a marker of a successful T-cell-macrophage interaction. It was found that when the recipient strain shared H-2 I-A region homology with the donor strain, enhanced antitularemic resistance was expressed, whereas homology at the H-2 K or D region was insufficient. Thus, macrophage--T-cell cooperation in immunity to experimental tularemia was restricted at the level of class II determinants.