Vascular endothelial growth factor (VEGF) is a secreted endothelial cell-specific mitogen, which is induced by hypoxia and is angiogenic in vivo. Recently, elevated serum concentrations of VEGF (S-VEGF) have been reported in patients with cancers of various histologies. However, the prognostic significance of S-VEGF in human cancer is unknown and the origin of S-VEGF remains unsettled. We measured S-VEGF by enzyme-linked immunosorbent assay from sera taken from 82 patients with non-Hodgkin's lymphoma before treatment and stored for 9 to 15 years at -20 degrees C. All but one of the patients had been followed-up for at least 5 years or until death. S-VEGF ranged from 15 to 964 pg/mL; median, 228 pg/mL; mean, 291 pg/mL. A higher than the median S-VEGF level was associated with a poor World Health Organization performance status, a high International Prognostic Index, a high serum lactate dehydrogenase level, and a large cell histology. Patients with lower than the median S-VEGF at diagnosis had a 71% 5-year survival rate in comparison with only 49% among those with a higher than the median S-VEGF. We conclude that a high pretreatment S-VEGF level is associated with poor outcome in non-Hodgkin's lymphoma.