We have studied tolerance onduction in transgenic CBA mice expressing H-2K^b genes under the influence of guinea-pig α-lactalbumln (KAL) or human β-globln gene promoter (Kβ). KAL radlo-reslstant cells, but not bone marrow derived cells, Induce tolerance to H-2K^b In chlmerlc mice. In contrast, bone marrow derived and radio-resistant cells of Kβ mice induce tolerance. Although appropriate, tissue-specific, expression of H-2K^b molecules occurs in KAL and Kβ mice, H-2K^b is expressed at low levels in thymus of transgenic mice. In addition, dendritic cells and macrophages express H-2K^b molecules when Kβ, but not when KAL bone marrow Is cultured in vitro. The mode of tolerance induction was examined in double transgenic mice by mating KAL or Kβ mice to mice expressing TCR transgenes (Tg-TCR) derived from a H-2K^b specific, CD8-independent cytotoxlc T cell clone. In both cases, a large number of Tg-TCR⁺ CD8⁺CD4⁺ thymocytes develop but mature CD8⁺CD4⁻ thymocytes fall to appear suggesting that thymocytes are eliminated late in development. Some CD8⁻CD4⁻ and CD8⁻CD4⁻ Tg⁻TCR⁺ T cells develop in double transgenic mice and respond to activation through their TCR – CD3 complex in vitro, although no responses to stimulation with H-2K^b expressing cells were detected. Thus, tolerance induction in KAL and Kβ mice proceeds via a deletlonal mechanism that is inefficient due either to low numbers of H-2K^b expressing thymic cells or to the low levels of H-2K^b expressed by thymlc cells, or to a combination of these factors.