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Background: Pruritus is identified as an adverse drug reaction to arsenic trioxide, but the association of arsenic exposure with pruritus has not been investigated. Methods: A cross‐sectional study was conducted in Shimen, China. A Mendelian randomization analysis was conducted to confirm the causal relationship between genetically predicted percentages of monomethylated arsenic (MMA%) and dimethylated arsenic (DMA%) in urine with chronic pruritus in UK Biobank. A case–control study was then conducted to determine the biomarker for pruritus. Arsenite‐treated mice were used to confirm the biomarker, and von Frey test was used to induce scratching bouts. Last, a randomized, double‐blind, placebo‐controlled trial was conducted to test the efficacy of naloxone in arsenic‐exposed patients with pruritus in Shimen. Results: Hair arsenic (μg/g) showed a dose–response relationship with the intensity of itch in 1079 participants, with odds ratios (OR) of 1.11 for moderate‐to‐severe itch (p = 0.012). The Mendelian randomization analysis confirmed the causal relationship, with ORs of 1.043 for MMA% (p = 0.029) and 0.904 for DMA% (p = 0.077) above versus under median. Serum β‐endorphin was identified as a significant biomarker for the intensity of itch (p < 0.001). Consistently, treatment with arsenite upregulated the level of β‐endorphin (p = 0.002) and induced scratching bouts (p < 0.001) in mice. The randomized controlled trial in 126 participants showed that treatment with sublingual naloxone significantly relieved the intensity of itch in arsenic‐exposed participants in 2 weeks (β = −0.98, p = 0.04). Conclusion: Arsenic exposure is associated with pruritus, and β‐endorphin serves as a biomarker of pruritus. Naloxone relieves pruritus in patients with arseniasis. [ABSTRACT FROM AUTHOR]