Differential gene expression analysis has the potential to illuminate fundamentals of biology by identifying key differences in transcription between cells, genotypes or diseases. I compared the expression profiles of 327 genes in a cohort of patients with head and neck cancer (1), grouped based on their survival at three years. Patients who were dead at three years possessed a unique “death signature” of forty genes whose expression was significantly different from that of survivors. This gene expression signature, associated with more rapid mortality in humans with head and neck cancer, may have clinical relevance in prognostic stratification and the genes themselves may have biological significance in the etiology of head and neck cancer.