OCT4 is a factor responsible for maintaining stemness. When expressed in embryonic stem cells, OCT4 induces self-renewal and pluripotency. However, OCT4 expression has also been linked to cancer progression in a variety of tumors. To determine which isoform is responsible for the modulation of head and neck cancer progression, the expression levels of OCT4A and OCT4B were measured. We found that while normal keratinocytes do not express OCT4, stem cells express OCT4A and cancer cells express OCT4B. Furthermore, the overexpression of OCT4A in a head and neck cancer cell line led to the activation of traits (such as increased proliferation) associated with poorer prognosis. We conclude that OCT4A may be the isoform responsible for the progression of head and neck cancer, and that it may serve as a marker of "cancer stem cells" thought to be the driving force behind metastasis and recurrence.