Abstract Cyclooxygenase (COX)-derived prostaglandin E2 (PGE2) plays a role in the development and progression of several tumor types including head and neck squamous cell carcinoma (HNSCC). Measurements of urinary PGE metabolite (PGE-M) can be used as an index of systemic PGE2 production. In ever smokers, increased levels of urinary PGE-M reflect increased COX-2 activity. In this study, we determined whether baseline levels of urinary PGE-M were prognostic for ever smoker HNSCC patients. A retrospective chart review of ever smoker HNSCC patients treated with curative intent was done. Fifteen of 31 evaluable patients developed progressive disease (recurrence or a second primary tumor) after a median follow-up of 38 months. There were no statistically significant differences between patients with (n = 15) or without disease progression (n = 16) with regard to stage, site, treatment received, smoking status, and aspirin use during follow-up. Median urinary PGE-M levels were significantly higher in HNSCC patients with disease progression (21.7 ng/mg creatinine) compared with patients without (13.35 ng/mg creatinine; P = 0.03). Importantly, patients with high baseline levels of urinary PGE-M had a significantly greater risk of disease progression (hazard ratio, 4.76, 95% CI, 1.31-17.30; P < 0.01) and death (hazard ratio, 9.54; 95% CI, 1.17-77.7; P = 0.01) than patients with low baseline levels of urinary PGE-M. These differences were most evident among patients with early-stage disease. Taken together, our findings suggest that high baseline levels of urinary PGE-M indicate a poor prognosis in HNSCC patients. Possibly, HNSCC patients with high COX-2 activity manifested by elevated urinary PGE-M will benefit from treatment with a COX-2 inhibitor.