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Purpose: To synthesize the available evidence on the extent to which area-level socioeconomic conditions are associated with drug overdose deaths in the United States. Methods: We performed a systematic review (in MEDLINE, EMBASE, PsychINFO, Web of Science, EconLit) for papers published prior to July 2022. Eligible studies quantitatively estimated the association between an area-level measure of socioeconomic conditions and drug overdose deaths in the US, and were published in English. We assessed study quality using the Effective Public Health Practice Project Quality Assessment Tool. The protocol was preregistered at Prospero (CRD42019121317). Results: We identified 28 studies that estimated area-level effects of socioeconomic conditions on drug overdose deaths in the US. Studies were scored as having moderate to serious risk of bias attributed to both confounding and in analysis. Socioeconomic conditions and drug overdose death rates were moderately associated, and this was a consistent finding across a large number of measures and differences in study designs (e.g., cross-sectional versus longitudinal), years of data analyzed, and primary unit of analysis (e.g., ZIP code, county, state). Conclusions: This review highlights the evidence for area-level socioeconomic conditions are an important factor underlying the geospatial distribution of drug overdose deaths in the US and the need to understand the mechanisms underlying these associations to inform future policy recommendations. The current evidence base suggests that, at least in the United States, employment, income, and poverty interventions may be effective targets for preventing drug overdose mortality rates. [ABSTRACT FROM AUTHOR]