Background. High circulating vascular endothelial growth factor (VEGF) levels tend to reflect tumor aggressiveness for being associated with tumor progression and prognosis. Measurement of soluble VEGF receptor-1 (sVEGFR-1) may improve diagnostic power of VEGF assay. Methods. This study investigated regulation of plasma VEGF by sVEGFR-1 in 82 patients with head and neck squamous cell carcinoma compared with 32 healthy subjects to obtain information for assay characterization. Results. Normality or abnormality of VEGF/sVEGFR-1secretion patterns was rated into five diagnostic levels from definitely abnormal (likelihood ratios) (LRs = 4–∞) to definitely normal (LRs = 0–0.17). Because of ineffective VEGF regulation, high grade tumor had a greater chance (62.5%) than low grade tumor (20%) in expressing a definitely abnormal pattern and a lower chance to express the normal pattern (P = 0.007). VEGF alone had much lower diagnostic power in differentiating between normal (LRs = 0.3–0.9) and abnormal secretion patterns (LRs = 2.2–2.4). Conclusions. VEGF dysregulation is suggestive of tumor aggressiveness for causing persistent plasma VEGF elevation. sVEGFR-1 improves diagnostic power of VEGF assay particularly in identifying subset of low grade tumor with underlying aggressive disease and ruling out aggressiveness in subset of high grade tumor.