Open Access Sphingosine kinase 1 (SphK1) is an important mediator of apoptosis and the proliferation of cancer cells. It is upregulated in cells showing increasing radioresistance. Here we present the correlation between SphK1 expression and survival outcomes in patients with carcinoma of the oral cavity. A retrospective chart review was performed between January 2009 and August 2010 at the University of Southern California. Patients diagnosed with an advanced-stage primary tumor restricted to the oral cavity and a minimum follow-up of two years were included. Patients who did not receive post-operative radiation therapy were excluded. Eighteen patients met the inclusion criteria with 10 (55.6%) patients demonstrating high expression of SphK1 and 8 (44.4%) patients demonstrating a low-to-moderate expression of SphK1. Tumor recurrence occurred in 9 patients (50.0%): 5 patients (27.8%) in the SphK1high cohort at a mean time to progression of 2.5 mo and 4 patients (22.2%) in the SphK1low cohort at a mean time to progression of 11.0 mo (p = 0.023). Death occurred in 8 patients (66.7%) in the SphK1high cohort and 3 patients (16.7%) in the SphK1low cohort (p = 0.036). Higher expression of SphK1 correlates with greater radioresistance and poorer survival outcomes in patients with HNSCC of the oral cavity.