Background Polymorphism of the serotonin transporter gene, 5-HTTLPR (short allele) has been associated with depression. The purpose of this study was to show the evaluated depression in patients with head and neck cancer and a possible association with the 5-HTTLPR. Methods The Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (SCID for DSM-IV) was administered to 94 patients with head and neck cancer, of which 33 patients were genotyped for 5-HTTLPR. We also evaluated the prevalence of 5-HTTLPR polymorphism in 121 patients with head and neck cancer and 97 controls. Results Forty-three percent of the patients met the criteria for a depressive diagnosis, 19% of which was new onset. In depressed patients, 85.7% (n = 12 of 14) had at least 1 short allele versus 68.4% (n = 13 of 19) of the patients without depressive diagnosis (p <.04). No difference was noted in the prevalence of the short allele in head and neck cancer cases versus controls (odds ratio = 0.8; p =.490). Conclusion Despite the high rate of depressive diagnosis, patients with head and neck cancer did not demonstrate a higher prevalence of this short allele of the 5-HTTLPR compared with a control population. Copyright © 2011 Wiley Periodicals, Inc.