Background/Aims: Vascular smooth muscle in Marfan syndrome, a connective tissue disorder caused by mutations in FBN1 encoding fibrillin-1, is associated with decreased tonic contraction. As Ca<sup>2+</sup> waves are tightly associated with vasoconstriction, we hypothesized decreased tonic contraction in Marfan syndrome is due to aberrant Ca<sup>2+</sup> wave signaling. Methods: Isometric force and intracellular Ca<sup>2+</sup> were measured from second-order mesenteric arteries from mice heterozygous for the Fbn1 allele encoding a cysteine substitution ( Fbn1<sup>C1039G/+</sup>). Results: Phenylephrine concentration-dependently induced tonic contraction associated with sustained repetitive oscillations in intracellular [Ca<sup>2+</sup>] in both control and Marfan vessels, although Marfan vessels displayed significantly decreased Ca<sup>2+</sup> wave frequency and decreased number of cells exhibiting waves. Inhibition of sarcoplasmic reticulum Ca<sup>2+</sup> re-uptake by cyclopiazonic acid abolished Ca<sup>2+</sup> waves, dramatically decreasing tonic contraction. Nifedipine significantly reduced Ca<sup>2+</sup> wave frequency and tonic contraction, while the nifedipine-insensitive component was abolished by SKF-96365. Ca<sup>2+</sup> waves and tonic contraction were abolished by 2-aminoethoxydiphenylborate, but were unaffected by ryanodine or tetracaine. Conclusion: Phenylephrine-induced Ca<sup>2+</sup> waves underlie tonic contraction in resistance-sized mesenteric arteries and appear to be produced by repetitive cycles of regenerative Ca<sup>2+</sup> release from the sarcoplasmic reticulum. Decreased frequency of Ca<sup>2+</sup> waves in Marfan syndrome appears to be responsible for reduced tonic contraction.