Head and neck squamous cell carcinoma (HNSCC) is a global malignancy. The insulin-like growth factor (IGF) signalling axis plays a critical role in tumourigenesis. This study defined the clinical and functional roles of insulin-like growth factor binding protein-5 (IGFBP-5) in HNSCC. Down-regulation of IGFBP-5 mRNA expression was found during the progression from pre-cancer to HNSCC. The down-regulation in HNSCC was associated with a higher propensity to nodal metastasis. SAS and OECM-1 are HNSCC cells that do, or do not, express IGFBP-5, respectively. Recombinant IGFBP-5 reduced the proliferation of OECM-1 cells and this was exerted mainly through blockade of the IGF pathways. Either IGFBP-5 or IGF-I treatment alone promoted OECM-1 migration, but a combination of treatments generated antagonistic effects. Overexpression of IGFBP-5 reduced the proliferation and anchorage-independent growth of both OECM-1 and SAS cells. Conversely, knockdown of IGFBP-5 expression significantly induced the proliferation and anchorage-independent growth of SAS cells. It also induced the growth of xenografted SAS tumours. SAS transfectants that expressed mutant or truncated IGFBP-5, which lack IGF binding activity, exhibited significantly lower anchorage-independent growth than vector control. This suggests that IGFBP-5 possesses an IGF-independent suppressor function. The suppressive effects of IGFBP-5 on the tumourigenesis of HNSCC might be invaluable to future neoplastic intervention.