Administration of 1, 2-dimethylhydrazine (DMH) induces intestinal epithelial tumors in mice. Increased numbers of mast cells have been reported to occur both within and near a variety of different neoplasms, including DMH-induced intestinal tumors. We investigated the role of the tyrosine kinase receptor, c-kit, and mast cells, in this model by administering DMH to c-kit mutant mast cell-deficient mice and the congenic normal mice. We attempted to induce colonic tumors by administering DMH (20 mg/kg body weight, sc, weekly for 20 weeks) to WBB6F1-Kit+/+(+/+) wild-type mice, the congenic mast cell-deficient WBB6F1-Kit W/Kit Wv (W/W v) mice and W/W v mice that had been repaired of their mast cell deficiency by adoptive transfer of bone marrow cells derived from the congenic+/+ mice. The susceptibility to the development of DMH-induced colonic tumors, and the numbers of mast cells associated with these tumors, was evaluated. Normal (+/+) mice exhibited significantly higher numbers of mast cells in DMH-induced intestinal tumors than in macroscopically normal colonic mucosa. Treatment with DMH induced development of colonic tumors in 97% of+/+ mice, but in only 32% of the W/W v mice. W/W v mice that had been repaired of their mast cell deficiency by transfer of+/+ bone marrow cells expressed susceptibility to the development of colonic tumors that was similar to that of wild-type mice. These results show that genetic impairment of c-kit function reduces the susceptibility of mice to DMH-induced colonic tumors, and that defects in bone marrow-derived cells in the W/W v mice contribute significantly to this result. Our findings also are consistent with the possibility that mast cells promote the development of DMH-induced colonic epithelial tumors in mice.