The neurodegenerative disorder Andermann syndrome is caused by mutations of the K-Cl co-transporter KCC3. Kcc3-knockout mice reproduce neurodegeneration and display arterial hypertension. Kcc3 is broadly expressed including the CNS and vascular smooth muscle cells. The intracellular chloride concentration of small arteries of Kcc3-/- mice was increased, which may influence myogenic tone and hence blood pressure. Isolated small arteries, however, reacted indistinguishably to changes in intravascular pressure, stimulation of alpha1-adrenoreceptors, exogenous nitric oxide or blockade of calcium-activated chloride channels. Likewise, the responses to alpha1-adrenergic stimulation or exogenous nitric oxide in vivo were identical in both genotypes. These results argue against a major vascular-intrinsic component of arterial hypertension. As either alpha1-adrenergic blockade or inhibition of ganglionic transmission abolished the difference in arterial blood pressure between both genotypes, a neurogenic origin is likely, which is further supported by an increase of urinary norepinephrine and epinephrine excretion in Kcc3-/- mice. Our data indicate that local control of myogenic tone does not require KCC3 and that hypertension in Kcc3-/- mice depends on an elevated sympathetic tone.