Desmoid tumors (aggressive fibromatosis) are locally invasive soft tissue tumors in which beta-catenin-mediated TCF-3-dependent transcription is activated. To provide more insight into the pathophysiology of these tumors, expression profiles were generated using oligonucleotide arrays (Affymetrix). In total, 69 differentially expressed genes were identified in desmoids compared to normal fibroblasts (fascia) from the same patients. The differential expression of a selection of genes was confirmed using RT-PCR and Northern blotting. We further evaluated the insulin-like growth factor-binding protein 6 (IGFBP-6), a gene that was consistently downregulated in all desmoids tested. Promotor studies and electromobility shift assays revealed two functional beta-catenin/TCF-responsive elements in the human IGFBP-6 promoter. These findings suggest that IGFBP-6 is directly downregulated by the beta-catenin/TCF complex in desmoid tumors, and imply a role for the IGF axis in the proliferation of desmoid tumors.