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In preclinical studies, \u03b2\u2010arrestin 2 has been implicated in \u00b5\u2010opioid receptor desensitization and internalization and the development of opioid tolerance and dependence. The present study investigated relationships between variants in the gene encoding \u03b2\u2010arrestin 2 (<jats:italic>ARRB2<\/jats:italic>) and clinically relevant phenotypes among individuals with opioid use disorder (OUD). We hypothesized that <jats:italic>ARRB2<\/jats:italic> variants would be associated with the negative effects of long\u2010term heroin use.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Chronic heroin users (<jats:italic>N<\/jats:italic>\u2009=\u2009201; <jats:italic>n<\/jats:italic>\u2009=\u2009103 African American; <jats:italic>n<\/jats:italic>\u2009=\u200998 Caucasian) were genotyped for <jats:italic>ARRB2<\/jats:italic> r1045280 (synonymous, also affecting binding motif of transcription factor GTF2IRD1), rs2036657 (3'UTR) and rs3786047 (intron) and assessed for the past\u2010month frequency of use, injection use, and lifetime duration of heroin use, number of heroin quit\u2010attempts, and heroin use\u2010related consequences.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Lifetime heroin\u2010use consequences (especially occupational and health\u2010related) were significantly lower for African American <jats:italic>ARRB2<\/jats:italic> r1045280 C\u2010allele carriers compared with\u00a0the TT genotype. There was no significant genotype difference in the Caucasian group. <jats:italic>ARRB2<\/jats:italic> rs2036657 was in strong linkage disequilibrium with rs1045280.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion and Conclusions<\/jats:title><jats:p>These results, consistent with extant data, illustrate a role for ancestry\u2010dependent allelic variation in <jats:italic>ARRB2<\/jats:italic> r1045280 on heroin\u2010use consequences. The <jats:italic>ARRB2<\/jats:italic> r1045280 C\u2010allele played a protective role in African\u2010descent participants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Scientific Significance<\/jats:title><jats:p>These first\u2010in\u2010human findings, which should be replicated, provide support for mechanistic investigations of <jats:italic>ARRB2<\/jats:italic> and related intracellular signaling molecules in OUD etiology, treatment, and relapse prevention. 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