Abstract—Clinical studies suggest that T-type Ca²⁺ channel blockade may have incremental benefits over conventional L-channel blockade, particularly in microvascular disorders. This study examined functional vasomotor differences in L- and T-channel blockade between large and small vessels and compared the abundance of the L- and T-type channels in these vessels. The inhibition of endothelin-1 and potassium-induced vascular contractile responses by L-channel blockers (verapamil and nifedipine) was compared with combined L- and T-channel blockers (mibefradil and efonidipine) in large (rat aorta) and small (rat mesenteric and human subcutaneous) vessels using wire myography. All 4 of the Ca²⁺ channel blockers inhibited contractile responses to a similar extent in large rat vessels; however, in rat microvessels, the combined L- and T-channel blockers produced significantly greater inhibition of contraction than L-channel blockers alone. The significance of this differential T-channel effect in microvessels was further supported by the following: (1) a greater abundance of T-channels compared with L-channels in microvessels but not in large vessels; (2) demonstration of divergent Ca²⁺ channel blocker responses in human microvessels; (3) incremental inhibition of constrictor responses with combined L- and T-Ca²⁺ channel blockers despite maximal L-channel blockade; (4) the use of structurally diverse Ca²⁺ channel blockers with varied affinity for L- and T-channels; (5) the use of pharmacodynamically and therapeutically appropriate Ca²⁺ channel blocker concentrations; (6) confirmation of contractile agonist independent responses; and (7) exclusion of an endothelium-dependent mechanism. We propose that T-type channels play an important role in regulating contractile responses in the microvasculature and, therefore, are a potential therapeutic target.