Previously we have cloned the human Frizzled 1 (HFz1) and shown that it transmits the Wnt-3a-induced canonical pathway. We also cloned the human Frizzled 6 (HFz6) and show in the present study that, as opposed to HFz1, HFz6 did not activate the canonical Wnt pathway following exposure to various Wnts, whether belonging to the Wnt-1 or to the Wnt-5a group. Moreover we show that HFz6 repressed Wnt-3a-induced canonical signaling when co-expressed with HFz1. HFz6 repressed the canonical Wnt cascade activated also by various Wnt signaling intracellular mediators such as Dishevelled-1, a stabilized β-catenin(S33Y) mutant, and LiCl-mediated repression of glycogen synthase kinase-3β activity. Removal of HFz6 N′- of C′-terminal sequences abolished HFz6 repressive activity. As the HFz6 repressive effect was not associated with a decrease in the level of β-catenin, it is suggested that HFz6 does not affect β-catenin stabilization, implying that HFz6 transmits a repressive signaling that cross-talks with and inhibits the canonical Wnt pathway downstream of β-catenin destruction complex. HFz6 did not affect the level of nuclear T-cell factor 4 (TCF4) nor did it affect β-catenin·TCF4 complex formation. However, electrophoretic mobility shift assays indicated that HFz6 repressed the binding of TCF/lymphoid enhancer factor transcription factors to target DNA. Moreover we present data suggesting that HFz6 activates the transforming growth factor-β-activated kinase-NEMO-like kinase pathway that blocks TCF/lymphoid enhancer factor binding to target promoters, thereby inhibiting the ability of β-catenin to activate transcription of Wnt target genes.