Metastatic renal cell carcinomas (RCC) remain highly resistant to systemic therapy. RCCs are highly vascular tumors, which overproduce angiogenic peptides such as vascular endothelial growth factor (VEGF) even under normoxic conditions. A potential suggested role of antiangiogenic therapeutic strategies is the treatment of RCC by inhibiting VEGF production. The down-regulation of VEGF expression by glucocorticoids has recently been demonstrated in several cells. In this study, the direct effects of glucocorticoids on VEGF production by RCC cells were evaluated. Four RCC cell lines A498, RCC270, Caki1, and ACHN were treated with dexamethasone (DEX), hydrocortisone (HC), 5-alpha-dihydrotestosterone (DHT), or estradiol (E2). RU486 was used as a glucocorticoid receptor (GR) antagonist. Cell growth was studied with MTS assays. VEGF mRNA and protein were evaluated with quantitative real-time RT-PCR and ELISA, respectively, and GR expression was examined using RT-PCR and immunocytochemistry. All four RCC cell lines expressed GR. DEX at 100 nM down-regulated VEGF secretions by more than 50% in three lines (A498, RCC270, and Caki1) and had a weak inhibitory effect on ACHN cells. The effect of DEX on reducing VEGF mRNA levels in A498 cells was concentration-dependent and maximal at 100 nM (80% inhibition). HC had similar but weaker effects on VEGF production in the RCC cells, but E2 and DHT had no effect. RU486 reversed the effects of DEX. DEX at 1-1000 nM did not affect cell growth in any of the four RCC cell lines. This is the first study showing that glucocorticoids, at concentrations achievable in vivo by oral administration of low doses of DEX, have an inhibitory effect on VEGF mRNA expression and protein secretion of RCC cells possibly through the GR pathway. Furthermore, DEX might have a potential role in antiangiogenic therapeutic strategies by inhibiting VEGF production during metastatic RCC treatment.