Fingolimod (FTY720) is a new immunosuppressant drug for the treatment of multiple sclerosis that, after phosphorylation in vivo, targets several sphingosine-1-phosphate (S1P) receptors. Phase III clinical trials revealed that this drug modestly increases blood pressure by 3–5 mmHg. Here we investigated whether Fingolimod and several derivatives have vasoactive properties that can account for this increase in blood pressure. For this purpose we studied contractile or dilatory responses to FTY720, its phosphorylated bioactive form FTY720-P, and derivatives of FTY720 (such as VPC23153, VPC24191 and VPC23019) in isolated rat mesenteric arteries and aorta. FTY720-P, but not its parent compound FTY720, induces vasoconstriction in rat mesenteric arteries most likely due to stimulation of S1P3 receptors in the smooth muscle. This constriction is partly counteracted by an endothelium-dependent vasodilation. In contrast, in rat aorta FTY720-P predominantly induces an endothelium-dependent vasodilation and no contractile properties were observed in this vessel type. Interestingly, closely related derivatives of Fingolimod all induce vasorelaxation in the two vascular beds, however, they do so by varying mechanisms. For instance, VPC24191 induces full, endothelium-independent relaxation in isolated mesenteric arteries, whereas in the aorta it induces a 50–60% endothelium-dependent relaxation. We conclude that FTY720-P has vasoactive properties that may favour vasoconstriction in resistance arteries, whereas closely related derivatives induce vasodilation in both mesenteric arteries and aorta. The divergent actions of FTY720 and its derivatives cannot be explained solely by receptor distribution and receptor selectivity of the compounds. This suggests that other mechanisms of actions partially account for the observed effects.