Over-expression of vascular endothelial growth factor A (VEGF-A) is correlated with leukemia metastasis. VEGF-A acts by binding to its membrane receptors R1 and R2 present in soluble forms (sVEGFR1, sVEGFR2) with different functions. sVEGFR could inhibit VEGF-A bioactivities, associated with favorable prognosis in solid tumors. However, its role is obscure in central nervous system leukemia (CNSL). The aim of this study was to investigate sVEGFR1, R2 as biomarkers in CNSL. Paired cerebrospinal fluid (CSF) and serum samples were collected from 35 leukemia cases with or without CNS metastasis. Levels of sVEGFR1 and sVEGFR2 in both CSF (sVEGFR1CSF, sVEGFR2CSF) and serum (sVEGFR1Serum, sVEGFR2Serum) were detected by ELISA. Other risk factors related to CNSL prognosis were also analyzed. sVEGFRSerum levels were 2.54-fold (sVEGFR1) and 25.6-fold (sVEGFR2) higher than sVEGFRCSF in both leukemic groups. sVEGFR1CSF in CNSL were 33 % higher than in the non-CNSL, and the levels of sVEGFR2CSF and sVEGFR2Serum had the same trend. Elevated sVEGFR1CSF and sVEGFR2CSF is closely correlated with blood-brain barrier (BBB) values and WBCCSF that is an indicator of CNSL disease burden. Cox regression analysis showed that the sVEGFR2CSF had a positive effect on event-free survival. Our data suggest that sVEGFR2CSF may be more potent than sVEGFR1CSF in predicting the outcome of leukemia patients, the balance between sVEGFR2CSF and VEGF-ACSF levels might be crucial for the progression of CNSL.