This study assessed two circulating angiogenic receptors as tumor markers in patients with head and neck squamous cell carcinoma (HNSCC): soluble vascular endothelial factor growth receptor-1 (sVEGFR1) and soluble Tie-2 receptor (sTie2R). Sera from 79 newly presenting patients with HNSCC and from 22 controls were assayed using sandwich ELISA. Median follow-up was 35 months after curative treatment. Analysis was carried out to compare levels between HNSCC patients and controls and to ascertain relationships with clinicopathologic and outcome variables. Soluble VEGFR1 was not elevated in the HNSCC group and was not related to any of the clinicopathologic or outcome variables. Soluble Tie2R was also not elevated in HNSCC patients or related to the clinicopathologic variables but was associated with locoregional recurrence (p =.009). Raised sTie2R (>64 ng/mL) independently predicted recurrence (p =.007) with a relative risk of 3.0 (95% CI, 1.7-5.0). Soluble Tie2R is an independent predictor of locoregional recurrence in HNSCC.