Squamous cell carcinoma of head and neck (SCCHN) is the most common cancer in the head and neck and is the sixth most common neoplasm worldwide. SCCHN has a high propensity to lymph node metastases, especially cancer of the pharynx. Prognosis of patients with SCCHN is severely influenced by the status of metastatic cervical lymph nodes and survival rates drop down to half when patients are presented with a metastatic node. The clinical relevance of heparanase as a prognostic marker in SCCHN was reported in several publications. Low levels of heparanase in SCCHN tumor cells was correlated with prolonged disease-free and overall survival. Furthermore, nuclear localization of heparanase predicts a favorable outcome compared to cytoplasmic localization. Heparanase staining was positively correlated with lymphatic vessel density and lymph node metastasis associated with the elevation of vascular endothelial growth factor C (VEGF-C). Heparanase ability to enhance phosphorylation of epidermal growth factor receptor (EGFR), and signal transducer and activator of transcription 3 (STAT3) were postulated to serve as critical molecular mechanisms by which heparanase facilitates tumor growth.Heparanase-2 (HPA2) is a close homolog of heparanase that lacks intrinsic HS-degrading activity but retains the capacity to bind HS with high affinity. HPA2 expression was markedly elevated in SCCHN patients, correlating with prolonged follow-up time to recurrence and inversely correlating with patients' N-stage. HPA2 appears to inhibit tumor dissemination, suggesting that HPA2 functions as a tumor suppressor. Thus, Heparanase and Heparanase-2 seem to exert opposing effects on SCCHN.