High VEGFC mRNA expression of AML blasts is related to increased in vitro and in vivo drug resistance. The prognostic significance of VEGFC on long-term outcome and its associated gene expression profiles remain to be defined. We studied the effect of VEGFC on treatment outcome and investigated gene expression profiles associated with VEGFC using microarray data of 525 adult and 100 pediatric AML patients. High VEGFC expression appeared strongly associated with reduced complete remission rate, reduced overall and event-free survival (OS and EFS) in adult AML. Multivariable analysis established high VEGFC as prognostic indicator independent of cytogenetic risk, FLT3-ITD, NPM1, CEBPA, age and WBC. Also in pediatric AML high VEGFC was related to reduced OS. A unique series of differentially expressed genes was identified that distinguished AML with high VEGFC from AML with low VEGFC, i.e., 331 upregulated genes (representative of proliferation, VEGF-receptor activity, signal transduction) and 44 downregulated genes (e.g. related to apoptosis) consistent with a role in enhanced chemoresistance. In conclusion, high VEGFC predicts adverse long-term prognosis and provides prognostic information in addition to well-known prognostic factors.