We investigated the immunohistochemical expression patterns of Frizzled homolog 10 (FZD10), a cell-surface receptor for molecules in the Wnt pathway, in tissue samples derived from 104 patients with colorectal cancers (CRCs). There was no immunoreactivity for FZD10 in normal colonic mucosa, and only tumor cells in polyps and CRC tissues showed spotted immunostaining patterns in apical sides of the cytoplasm. In metastatic liver lesions, tumor cells showed cytoplasmic immunostaining similar to primary lesions, whereas normal liver parenchyma showed almost no immunostaining. Frequencies of FZD10-immunopositive cells in tumor tissues were significantly higher in CRCs than those in polyps (3.3 +/- 10.3% vs 20.5 +/- 31.7%, P = 0.0016), and almost equivalent with those in metastatic liver lesions (33.2 +/- 39.7% vs 26.4 +/- 33.4%, P = 0.133). Analyses of paired samples (polyps and CRCs, or CRCs and metastatic liver lesions from the same patient) suggested that a subset of CRCs possessed intrinsic genetic mechanisms causing the evolution of FZD10-positive clones during tumor progression, making FZD10 a promising candidate for molecular imaging and a target for therapy. To our surprise, cancer cells immunopositive for FZD10 showed significantly less nuclear accumulation of beta-catenin, compared to FZD10-immunonegative cancer cells, and there was a strong inverse correlation between nuclear immunostaining scores for beta-catenin expression and expression patterns of FZD10 (P = 0.0002), suggesting that FZD10 has a distinct role from other FZDs in canonical Wnt signal transduction.