Although the Mas-related G-protein-coupled receptors (Mrgprs) play essential roles in itch detection, their contribution to allergic contact dermatitis (ACD) associated itch remains unclear.To investigate whether Mrgprs are involved in ACD and whether Mrgprs can be identified as potential therapeutic targets.Mrgpr-clusterΔ-/- mice and human MrgprX1 (hMrgprX1) transgenic mice were applied to evalute the function of Mrgprs in oxazolone-induced ACD.Utilizing ACD model, we find that Mrgpr-clusterΔ-/- mice display significantly reduced pruritus. Among 12 Mrgprs deleted in Mrgpr-clusterΔ-/- mice, the expression of MrgprC11 and MrgprA3 are significantly increased in ACD model, which also innervate the skin and spinal cord at higher-than-normal densities, the proportions of dorsal root ganglia neurons responding to bovine adrenal medulla peptide 8-22 and chloroquine are also remarkably increased in ACD model and result in enhancing itch behavior. To study the function of human Mrgprs in ACD-induced itch, we utilize hMrgprX1 transgenic mice, which rescues the severe itch defect of Mrgpr-clusterΔ-/- mice in ACD model. Remarkably, pharmacological blockade of hMrgprX1 significantly attenuates ACD itch in hMrgprX1 transgenic mouse.Our study provides the first evidence that Mrgprs are involved in ACD induced chronic itch, which provides new avenues for itch management in ACD. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.