In the past decade cancer, including head and neck squamous cell cancer (HNSCC), is increasingly being regarded as a stem cell associated disease which arises from cells with the property of stemness. According to the cancer stem cell (CSC) theory, only a specific subpopulation of cancer cells has the ability to initiate and perpetuate cancer growth, especially under treatment. In this article we describe a subpopulation of cells within HNSCC that expresses the stemness factor Oct-4, which leads to apoptotic resistance after exposure to chemotherapeutic agents.Permanent cell lines and HNSCC tissue were analyzed for expression of stem cell markers using flow cytometric, immunohistochemical approaches and an antibody based protein array. Chemotherapeutic agent-induced growth inhibition, also known as "enrichment", was determined by the colorimetric cell proliferation assay (MTT-based) and putative stem cell markers were investigated by flow cytometry.Various potential CSC markers were identified in heterogenic expression profiles in permanent cell lines and solid tumors. Our data suggest the Oct-4A isoform as a marker of stemness in HNSCC and the enrichment of cancer stem-like cells by various chemotherapeutic agents was associated with a significantly higher expression of Oct-4.This data suggests that many potential CSC markers are expressed on different expression levels in HNSCC. Among these markers Oct-4(A) plays a pivotal role in the detection of cancer cells with enhanced chemoresistance and provide evidence for the existence of cancer stem-like cells in HNSCC.