The Cdx1 homeobox gene encodes an intestine-specific transcription factor with a pro-oncogenic function in vitro. Here we have analysed the pattern of Cdx1 in human colon cancer progression. Cdx1 expression remains at a high level in the majority of the polyps and it is even overexpressed in more than one-third of the specimens, consistent with the fact that the gene is an intestine-specific target of oncogenic pathways. However, Cdx1 decreases in one-fifth of the polyps, which is reminiscent of the loss of expression previously reported in the majority of carcinomas. Allelic imbalance analysis demonstrates that the Cdx1 locus located on chromosome 5q is a major site of genomic rearrangement in colorectal cancers, and that the frequency of the rearrangements increases during polyps to carcinoma progression. Allelic imbalance at the Cdx1 locus occurs in relation to, although not invariably in association with, the rearrangements at the APC locus on the same chromosomal arm. Xenografts of primary human colon carcinomas indicate that the level of Cdx1 mRNA correlates with the intensity of allelic imbalance. Together, these data show that Cdx1 exhibits a complex pattern during colorectal cancer progression. Given that Cdx1 has a pro-oncogenic function in vitro, the maintenance of a high level of expression in polyps, and even its overexpression in one-third of the specimens, suggest that this homeobox gene may be an important factor in the process toward malignant transformation during the first steps of tumorigenesis.