Objective—To compare responses of equine digital arteries (EDAs) and veins (EDVs) to human-acalcitonin gene-related peptide (hαCGRP), evaluate effect of the endothelium, and characterize receptors and sources of endogenous CGRP. Sample—Palmar digital vessels (5 to 9/experiment) from healthy adult horses killed at an abattoir. Procedures—Vessel rings were mounted under tension in organ baths containing Krebs-Henseleit solution at 30°C, with relaxation responses examined in vessels preconstricted with a thromboxane-mimetic (3 × 10(−8)M). Responses of endothelium-intact (+e) and -denuded (−e) EDAs and EDVs to hαCGRP C10−10 to 3 × 10(−7)M) were compared. Following incubation with an hαCGRP receptor antagonist (hαCGRP8–37; 1μM), responses of EDA(−e) and EDV(−e) to hαCGRP (10(−7)M) were obtained. Responses of endothelium-intact and -denuded arteries and veins to hαCGRP (3 × 10(−7)M) or capsaicin (10(−5)M) were evaluated as well as responses of endothelium-intact and -denuded EDA and EDV to hαCGRP (10(−10) to 10(−6)M) after incubation with endothelin-1 (ET-1; 10(−12)M). Results—hαCGRP resulted in nonendothelium, concentration-dependent relaxation in EDAs and EDVs, with greater responses in EDAs. Treatment with hαCGRP8–37 had minimal effect on responses to hαCGRP in either vessel type. Capsaicin induced relaxation in both vessel types. There were no differences between responses to hαCGRP for vessels pretreated with ET-1 or vehicle. Conclusions and Clinical Relevance—Both hαCGRP and capsaicin induced digital vasodilation unaffected by a functional endothelium. This suggested that endogenous CGRP likely emanates from sensory-motor nerves and may contribute to digital vasodilation.