Autocrine/paracrine stimulation of KIT has been observed in colorectal carcinoma (CRC) cell lines. We investigated the expression of KIT and stem cell factor (SCF) in CRC in comparison with premalignant colon lesions and normal colonic mucosa to assess the prognostic and therapeutic relevance of this receptor/ligand system in CRC. Transcript levels of c-kit and the two SCF splicing variants were determined quantitatively by real-time RT-PCR using cDNA obtained from normal, premalignant and malignant snap frozen colon tissue specimens. Immunohistochemistry with specific anti-KIT and anti-SCF antibodies was performed on paraffin-embedded tissue sections in order to localize the relative protein expression in epithelial compartments. Approximately 10% of patients expressed KIT in their adenoma or primary tumor. The majority of KIT-positive carcinomas co-expressed SCF. Real-time RT-PCR showed expression of c-kit and SCF transcripts in all cDNA specimens examined. A significant association between the co-expression of KIT/SCF and a worse clinical outcome was found. In conclusion, KIT expression was observed in a proportion of premalignant and malignant colonic lesions, while it was virtually absent in normal colon mucosa. Moreover, the majority of KIT-positive carcinomas co-expressed SCF, suggesting the possibility of aberrant signaling by an autocrine loop, as confirmed by the negative prognostic value of this association. Therefore, in the subset of CRC patients with concomitant KIT/SCF expression, the activity of Imatinib mesylate, a selective inhibitor of specific tyrosine kinases including KIT, may be exploited in combination with standard therapy.