Patients who develop squamous cell carcinoma of the head and neck (SCCHN) are often malnourished because of poor dietary habits, excessive alcohol consumption, local tumor effects, tumor-induced cachexia, and the effects of various therapies. The composition of the diet may be a risk factor for the development of head and neck cancer as well as tumor progression. This study compares the amino acid profiles in the banked serum of patients with and without SCCHN. In comparison to the control group, patients with SCCHN had significantly decreased preoperative serum levels of alanine (p = 0.006), asparagine (p = 0.002), aspartic acid (p = 0.0001), glycine (p = 0.0002), histidine (p = 0.002), 3-methylhistidine (p = 0.001), ornithine (p = 0.001), phenylalanine (p = 0.002), serine (p = 0.002), taurine (p < 0.0001), and threonine (p = 0.001). Levels of cystine were significantly elevated in the group of cancer patients (p < 0.0001). No significant differences were noted on the basis of T stage, N stage, or nutritional status. Serum levels increased postoperatively for the majority of the amino acids tested. Postoperative histidine levels were associated with tumor recurrence (p = 0.04). Serum amino acid levels may prove to be useful markers of disease status and provide prognostic information.