The diverse receptor-ligand pairs of the Wnt and frizzled (Fz) families play important roles during embryonic development, and thus may be overexpressed in cancers that arise from immature cells. Hence, we investigated the expression and function of five Wnt (Wnt-1, 5a, 7a, 10b, 13) and two Fz (Fz-2, 5) genes in 10 head and neck squamous carcinoma cell lines (HNSCC). In comparison to normal bronchial or oral epithelial cells, all the HNSCC had markedly increased mRNA levels of Wnt-1, 7a, 10b, and 13, as well as Fz-2. Moreover, the levels of Wnt-1, 10b, and Fz-2 proteins were also markedly increased in HNSCC, relative to normal epithelial cells. Treatment of one HNSCC cell line (SNU 1076) with anti-Wnt-1 antibodies reduced the activity of the Wnt/Fz dependent transcription factor LEF/TCF, and diminished the expression of cyclin D1 and beta-catenin proteins. Blocking Wnt-1 signaling also inhibited proliferation and induced apoptosis in these cells. These results show that HNSCC cell lines often overexpress one or more Wnt and Fz genes, and suggest that the growth and survival of a subset of HNSCC may depend on the Wnt/Fz pathway. Hence, the Wnt and Fz receptors may be possible targets for immunotherapy therapy of this common cancer.