Objective: Perivascular adipose tissue secretes an adipocyte-derived relaxing factor (ADRF) that opens voltage-dependent potassium (Kv) channels in peripheral arteries. We studied the role of KCNQ-type Kv channels and tested the hypothesis that hydrogen sulfide (H₂S) could be an ADRF. Methods: We performed isometric contraction studies on systemic arteries of rats and mice. Results: In mesenteric arteries, gracilis muscle arteries, and aortas without perivascular adipose tissue, the KCNQ channel openers retigabine, VRX0530727, VRX0621238, and VRX0621688 produced concentration-dependent vasorelaxation; VRX0621688 was the most potent vasodilator. The KCNQ channel inhibitor XE991 (30 mM) blocked the effects of both the drugs and ADRF. Inhibitors of cystathionine gamma lyase (CSE) ß-cyano-L-alanine (BCA, 5 mM) and 4-propargyl glycine (PPG, 10 mM) also blocked the relaxations. Cystathionine gamma lyase is expressed in perivascular adipose tissue and endogenously generates H₂S. The H₂S donor NaHS produced concentration-dependent vasorelaxation, which was also blocked by XE991. The vasodilatory capacities of retigabine, VRX0530727, VRX0621238, and VRX0621688 were preserved following inhibition of H₂S generation in perivascular fat. Conclusion: We suggest that KCNQ channel opening is a powerful mechanism to produce vasorelaxation of systemic arteries in rats and mice. Furthermore, KCNQ channels play a major role in the paracrine control of vascular tone by perivascular adipose tissue, which is at least in part mediated or modulated by H₂S. In conditions of reduced H₂S release from perivascular adipose tissue, these paracrine effects can be mimicked by synthetic KCNQ channel openers.